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Sixth Edition
Volume 6: Nervous System Agents

Edited by

Donald j. Abraham
Department of Medicinal Chemistry
School of Pharmacy
Virginia Commonwealth University
Richmond, Virginia

A john Wiley and Sons, Inc., Publication


AGENTS, 1 Vida International Pharmaceutical
Robert K. Griffith Consultants
West Virginia University Greenwich, Connecticut
School of Pharmacy Joseph Yevich
Morgantown, West Virginia Pharmaceutical Research Institute
Bristol-Myers Squibb Company
2 CHOLINERGICS, 39 Wallingford, Connecticut
Joseph G. Cannon
The University of Iowa 6 ANTICONVULSANTS, 263
Iowa City, Iowa Kenneth R. Scott
School of Pharmacy
3 ANTICHOLINERGIC DRUGS, 109 Howard University
Washington, DC
B. V . Rama Sastry
School of Medicine
Vanderbilt University 7 NARCOTIC ANALGESICS, 329
Nashville, Tennessee Jane V . Aldrich
Sandra C. Vigil-Cruz
4 CNS STIMULANTS, 167 Department of Medicinal Chemistry
School of Pharmacy
David E. Nichols University of Kansas
Department of Medicinal Chemistry Lawrence, Kansas
Molecular Pharmacology
School of Pharmacy and Pharmacal
Purdue University
Indiana, West Lafayette

xiv Contents


Leslie Iversen PARKINSON'S DISEASE, 711
University of Oxford
Department of Pharmacology John L. Neumeyer
Oxford, United Kingdom Ross J. Baldessarini
Harvard Medical School
Richard A. Glennon McLean Hospital
Virginia Commonwealth University Belmont, Massachusetts
School of Pharmacy
Richmond, Virginia Raymond G. Booth
School of Pharmacy
The University of North Carolina
9 ANTIANXIETY AGENTS, 525 Chapel Hill, North Carolina
Kevin S. Currie
Neurogen Corporation 13 ALZHEIMER'S DISEASE:
Branford, Connecticut SEARCH FOR THERAPEUTICS,
10 ANTIPSYCHOTIC AGENTS, 599 W. Janusz Rzeszotarski
Food and Drug Administration
C. Anthony Altar Rockville, Maryland
Psychiatric Genomics, Inc.
Department of Gene Discovery
Gaithersburg, Maryland 14 COGNITION ENHANCERS, 779

Arnold R. Martin Clark N. Eid, Jr.

University of Arizona Yong-Jin Wu
Department of Pharmacology Division of Central Nervous System
College of Pharmacy
Bristol-Myers Squibb
Tucson, Arizona
Pharmaceutical Research Institute
Andrew Thurkauf Wallingford, Connecticut
Neurogen Corporation Gene G. Kinney
Department of Medicinal Chemistry Department of Neuroscience
Branford, Connecticut Merck Research Laboratories
West Point, Pennsylvania
James David Adams Jr. DISORDERS, 837
Department of Molecular Philip A. Carpino
Pharmacology and Toxicology John R. Hadcock
USC School of Pharmacy Pfizer Global Research &
Los Angeles, California Development-Groton Labs
Thomas F. Woolf Department of Cardiovascular and
HyBar BioScience, LLC Metabolic Diseases
Ann Arbor, Michigan Groton, Connecticut

INDEX, 895

Adrenergics and Adrenergic-

Blocking Agents
School of Pharmacy
West Virginia University
Morgantown, West Virginia

1 Introduction, 2
2 Clinical Applications, 2
2.1 Current Drugs, 2
2.1.1 Applications of General Adrenergic
Agonists, 9
2.1.2 Applications of a,-Agonists, 12
2.1.3 Applications of a,-Agonists, 13
2.1.4 Applications of p-Agonists, 14
2.1.5 Applications of Antiadrenergics, 14
2.1.6 Applications of Nonselective a-
Antagonists, 15
2.1.7 Applications of Selective a,-
Antagonists, 15
2.1.8 Applications of p-Antagonists,16
2.1.9 Applications of alp-Antagonists, 16
2.1.10 Applications of Agonists/Antagonists,
2.2 Absorption, Distribution, Metabolism, and
Elimination, 16
2.2.1 Metabolism of Representative
Phenylethylamines, 16
2.2.2 Metabolism of Representative
Imidazolines and Guanidines, 18
2.2.3 Metabolism of Representative
Quinazolines, 19
2.2.4 Metabolism of Representative Aryl-
oxypropanolamines, 19
3 Physiology and Pharmacology, 21
3.1 Physiological Significance, 21
3.2 Biosynthesis, Storage, and Release
of Norepinephrine, 22
3.3 Effector Mechanisms
Burger's Medicinal Chemistry and Drug Discovery of Adrenergic Receptors, 25
Sixth Edition, Volume 6: Nervous System Agents 3.4 Characterization of Adrenergic
Edited by Donald J. Abraham Receptor Subtypes, 25
ISBN 0-471-27401-1 02003 John Wiley & Sons, Inc. 4 History, 26
Adrenergics and Adrenergic-Blocking Agents

5 Structure-Activity Relationships, 28 5.1.5 Imidazolines and Guanidines, 30

5.1 Phenylethylamine Agonists, 28 5.1.6 Quinazolines, 31
5.1.1 R1 Substitution on the Amino Nitrogen, 5.1.7 Aryloxypropanolamines, 32
28 6 Recent Developments, 33
5.1.2 R2 Substitution a to the Basic 6.1 Selective a,-Adrenoceptor Antagonists, 33
Nitrogen, Carbon-2,28 6.2 Selective P,-Agonists, 34
5.1.3 R3 Substitution on Carbon-1, 29
5.1.4 R4 Substitution on the Aromatic Ring,

1 INTRODUCTION subdivided. Identification of subclasses of adre

noceptors has been greatly aided by the tools of
In both their chemical structures and biologi- molecular biology and, to date, six distinct a-ad-
cal activities, adrenergics and adrenergic- renoceptors (a,,, a,,, a,,, ~ Z A ~, Z B ,aZd,and
blocking agents constitute an extremely var- three distinct P-adrenoceptors (PI, P,, P,) have
ied group of drugs whose clinical utility been clearly identified (I), with conflicting evi-
includes prescription drugs to treat life- dence for a fourth type of /3 (P,) (13). In general
threatening conditions such as asthma and the most common clinical applications of a,-ago-
hypertension as well as nonprescription med- nists are as vasoconstrictors employed as nasal
ications for minor ailments such as the com- decongestants and for raising blood pressure in
mon cold. This extensive group of drugs in- shock; a,-agonists are employed as antihyper-
cludes synthetic agents as well as chemicals tensives; a,-antagonists (a-blockers) are vasodi-
derived from natural products that have been lators and smooth muscle relaxants employed as
used in traditional medicines for centuries. antihypertensives and for treating prostatic hy-
Many adrenergic drugs are among the most perplasia; p-antagonists (p-blockers) are em-
commonly prescribed medications in the ployed as antihypertensives and for treatingcar-
United States, including bronchodilators, diac arrhythmias; and p-agonists are employed
such as albuterol (13) for use in treating as bronchodilators. The most novel recent ad-
asthma, and antihypertensives, such as ateno- vances in adrenergic drug research have been
lo1 (46) and doxazosin (42). Nonprescription directed toward development of selective p,-ago-
adrenergic drugs include such widely used na- nists that have potential applications in treat-
sal decongestants as pseudoephedrine (5)and ment of diabetes and obesity (4-8).
naphazoline (29). Most of these varied drugs
exert their therapeutic effects through action
on adrenoceptors, G-protein-coupled cell sur-
face receptors for the neurotransmitter nor-
2.1 Current Drugs
epinephrine (noradrenaline, I), and the adre-
nal hormone epinephrine (adrenaline, 2). U.S. Food and Drug Administration (FDA)-
approved adrenergic and antiadrenergic drugs
currently available in the United States are
summarized in Table 1.1, which is organized
in general according to pharmacological mech-
anisms of action and alphabetically within
those mechanistic classes. Structures of the
currently employed drugs are given in Tables
1.2-1.6 according to chemical class. Drugs in a
(1) norepinephrine, R = H given mechanistic class often have more than
(2) epinephrine, R = CH3
one therapeutic application, and may or may
not all be structurally similar. Furthermore,
Adrenoceptors are broadly classified into a- drugs from several different mechanistic
and preceptors, with each group being further classes may be employed in a given therapeu-
Table 1.1 Adrenergic and Antiadrenergic Pharmaceuticals
Class and Generic Name Trade Namea Originator Chemical Class Dosebc
General agonists
Amphetamine ( 3 ) Adderall, Dexedrine SmithKline & French Phenylethylamine 5-60 mglday
Dipivefrin ( 4 ) Propine Klinge Phenylethylamine 1 drop 2 X daily 0.1% soln.
Ephedrine erythro-(5) various Phenylethylamine 50-150 mglday for asthma
10-25 mg i.v. for hypotension
Epinephrine ( 2 ) Adrenaline Parke-Davis Phenylethylamine 0.3-1.5 mg S.C.
2-10 pglmin i.v.
160-250 pg inh.
Mephentermine ( 6 ) Wyamine Wyeth Phenylethylamine 30-45 mg, i.m.
Norepinephrine (1) Levophed Sterling Phenylethylamine 0.5-30 pglmin i.v.
Pseudoephedrine threo- various Phenylethylamine 60-240 mglday
Levonordefrin ( 7 ) na Winthrop Phenylethylamine 1:20,000 in local anesthetics
Metaraminol(8) Aramine Sharpe & Dohme Phenylethylamine 2-10 mg, i.m.
w Methoxamine ( 9 ) Vasoxyl Burroughs Wellcome Phenylethylamine 10-20 mg, i.m.
Midodrine (10) Prohatine Oesterreichische Phenylethylamine 30 mglday
Naphazoline (29) various Ciba Imidazoline 1-2 drops 0.05% nasal
0.03% ophthalmic
Oxymetazoline (30) various Merck Imidazoline 1-2 drops 0.05% nasal
0.025% ophthalmic
Phenylephrine (11) various F. Stearns & Co. Phenylethylamine 1-3 drops
0.25-0.5% soln. nasal
0.1-0.5 mg i.v. for shock
Tetrahydrozoline (31) Various Sahyun Imidazoline 1-2 drops of 0.05%.soln.
Xylometazoline (32) Ciba Imidazoline 2-3 drops of 0.1% soln.
Apraclonidine (33) Iopidine Alcon Aminoimidazoline 3-6 drops 0.51% soln.
Brimonidine (34) Alphagan Pfizer Aminoimidazoline 1 drop 0.2% soln., 3 x daily
Clonidine (35) Catapress Boehringer Aminoimidazoline 0.2-1.2 mglday
Guanabenz (36) Wytensin Sandoz Arylguanidine 8-32 mglday
Guanfacine (37) Tenex Wander Arylguanidine 1-3 mglday
Methyldopa (12) Aldomet Merck Aromatic amino acid 500-2000 mglday
Table 1.1 (Continued)
Class and Generic Name Trade Namea Originator Chemical Class Dosebc

Proventil, Ventolin Allen & Hanburys Phenylethylamine 12-32 mg/day p.0.

2.5 mg 3 4 X daily, neb.
Bitolterol(14) Tornalate Sterling Phenylethylamine 0.74-2.22 inh.
Formoterol(15) Foradil Yamanouchi Phenylethylamine 12 pg, 2 x daily inh.
Isoetharine (16) Bronkosol I. G. Farben Phenylethylamine 2 mL 0.25% soln. inh.
Isoproterenol(l7) Isuprel Boehringer Phenylethylamine 120-262 pg, 24% daily inh.
0 5 5 . 0 pg/min, i.v.
Xopenex Sepracor Phenylethylamine 0.63-1.25 mg 3X daily neb.
Alupent, Metaprel Boehringer Phenylethylamine 60-80 mg/day p.0.
1.3-1.95 mg, M x daily, inh.
Maxair Pfizer Pyridylethylamine 0.2-0.4 mg 4-6X daily, inh.
Yutopar Philips Phenylethylamine 150-350 pg/min, i.v.
120 mglday
Salmeterol(21) Serevent Glaxo Phenylethylamine 42 pg, 2X daily, inh.
Terbutaline (22) Brethine Draco Phenylethylamine 7.5-15 mg/day
Guanadrel(38) Hylorel Cutter Guanidine 10-75 mglday
Guanethidine (39) Ismelin Ciba Guanidine 10-50 mg/day
Reserpine (60) reserpine Ciba Alkaloid 0.05-0.5 mg/day
Metyrosine (23) Demser Merck Aromatic amino acid 14 g/day
Dapiprazole (61) Rev-Eyes Angelini-Francesco Piperidinlytriazole 2 drops 0.5% soln.
Phenoxybenzamine (62) Dibenzylime SmithKline & French Haloalkylamine 20-120 mglday
Phentolamine (40) Regitine Ciba Imidazoline 5-10 mg i.v.
Tolazoline (41) Priscoline Ciba Imidazoline 40-200 mg/day
Doxazosin (42) Cardura Pfizer Quinazoline 1-16 mg/day
Prazosin (43) Minipress Pfizer Quinazoline 1-9 mglday for BPH
6-20 mglday for hypertension
Tamsulosin (24) Flomax Yamanouchi Phenylethylamine 0.4-0.8 mg/day
Terazosin (44) Hytrin Abbott Quinazoline 5-20 mg/day
Sectral May & Baker Aryloxypropanolamine 200-1200 mglday
Tenormin ICI Aryloxypropanolamine 25-150 mglday
Betoptic, Kerlone Synthelabo Aryloxypropanolamine Hypertension: 10-20 mg orally
Glaucoma: 1-2 drops 0.5% soh. 2 x daily
Bisoprolol(48) Zebeta Merck Aryloxypropanolamine 1.25-20 mglday
Carteolol(49) Cartrol, Ocupress Otsuka Aryloxypropanolamine 2.5-10 mglday
Esmolol(50) Brevibloc American Hospital Supply Aryloxypropanolamine 50-100 pg/kg/min
Levobetaxolol S-(-1447) Betaxon Alcon Aryloxypropanolamine 1 drop 0.5% soln., 2X daily
Levobunolol (51) Betagan Warner-Lambert Aryloxypropanolamine 1-2 drops 0.5% soln., 1-2X daily
Metipranolol (52) OptiPranolol Boehringer Aryloxypropanolamine 1 drop 0.3% soln.., 2 x daily
Metoprolol(53) Lopressor, Toprol-XL AB Hksle Aryloxypropanolamine 100-450 mglday
Toprol-XL XL 50-100 mglday
Corgard Squibb Aryloxypropanolamine 40-320 mglday
Levatol Hoechst Aryloxypropanolamine 20-80 mglday
Visken Sandoz Aryloxypropanolamine 10-60 mglday
Inderal, Inderal LA ICI Aryloxypropanolamine 160-640 mglday
Betapace Mead Johnson Phenylethylamine 160-320 mglday
Timoptic Frosst Aryloxypropanolamine Hypertension: 10-60 mglday
Glaucoma: 1 drop 0.25% soln., 2X daily
Carvedilol(59) Coreg Boehringer Aryloxypropanolamine 13-50 mglday
Labetalol(26) Normodyne Allen & Hanburys Phenylethylamine 200-2400 mglday
Dobutamine (27) Dobutrex Lilly Phenylethylamine 2-20 pgkglmin, i.v.
- (28) Vasodilan Philips Arylpropanolamine 30-80 mglday

"Not all trade names are listed, particularly for drugs no longer under patent.
bAU dose information from Drug Facts a n d Comparisons 2002(14).
"Not all doses and dosage forms are listed. For further information consult reference (14).
Table 1.2 Phenylethylamines (Structures 1-28)

4' \
Compound R1 R2 R3 R4 Receptor Activity"
(1) H H OH 3',4'-diOH a+@
(2) CH3 H OH 3',4'-diOH pza!
(3) H CH3 H H (a! + mb
(4) CH3 H OH 3',4'-di-02CC(CH3), (P 2 a!)"
(5) CH3 CH3 OH H (a! + P ) ~
(6) cH3 2,2-diCH3 OH H (a + PIb
m (7) H CH3 OH 3',4'-&OH a
(8) H CH3 OH 3'-OH a!

(9) H CH3 OH 2',5'-diOCH3 a!

(10) COCH,NH2 H OH 2',5'-diOCH3 a!
(11) CH3 H OH 3'-OH a
(12) H 2-CH,, 2-C02H H 3',4'-&OH azC
(13) C(CH3)3 H OH 3'-CH20H, 4'-OH Pz
(14) C(CH3I3 H OH 3',4'-bis(02CC,H4-p-CH,) Pzc
(15) H OH 3'-NHCHO, 4'-OH


(16) CH(CH3I2 CH2CH3 OH 3',4'-diOH P
(17) CH(CH& H OH 3',4'-&OH P
(18) C(CH& H OH 3',5'-diOH P2
(19) C(CH3I3 H OH 2'-aza, 3'-CH20H, 4'-OH PZ
(20) cH3 OH 4'-OH P2

"Agonist activity unless indicated otherwise.
bIndirectactivity through release of norepinephrine and reuptake inhibition.
dMixeddirect and indirect activity.
'Norepinephrine biosynthesis inhibitor.
fNet sum of effects of enantiomers.
8 Adrenergics and Adrenergic-Blocking Agents

Table 1.3 Imidazolines and Guanidines (Structures 29- 41)

Compound Structure Receptor Activity
2 Clinical Applications

Table 1.3 (Continued)

Compound Structure Receptor Activity

"Inhibit release of norepinephrine.

tic application; for example, p-blockers, a,- raises blood pressure, (1)is used to counteract
blockers, and a,-agonists are all employed to various hypotensive crises and as an adjunct
treat hypertension. treatment in cardiac arrest where its p-activ-
ity stimulates the heart. Although it also lacks
2.1.1 Applications of General Adrenergic oral activity because it is a catechol, epineph-
Agonists. The mixed a- and p-agonist norepi- rine (2) is far more widely used clinically than
nephrine (1)has limited clinical application (1).Epinephrine, like norepinephrine, is used
because of the nonselective nature of its action to treat hypotensive crises and, because of its
in stimulating the entire adrenergic system. greater p-activity, is used to stimulate the
In addition to nonselective activity, it is orally heart in cardiac arrest. When administered in-
inactive because of rapid first-pass metabo- travenously or by inhalation, epinephrine's
lism of the catechol hydroxyls by catechol-0- &activity makes it useful in relieving bron-
methyl-transferase (COMT) and must be ad- choconstriction in asthma. Because it has sig-
ministered intravenously. Rapid metabolism nificant a-activity, epinephrine is also used in
limits its duration of action to only 1 or 2 min, topical nasal decongestants. Constriction of
even when given by infusion. Because its a-ac- dilated blood vessels by a-agonists in mucous
tivity constricts blood vessels and thereby membranes shrinks the membranes and re-
10 Adrenergics and Adrenergic-Blocking Agents

Table 1.4 Quinazolines (Structures 42-44)

Compound R Receptor Activity

duces nasal congestion. Dipivefrin (4) is a pro- mic mixture of R,R and S,S stereoisomers.
drug form of (2), in which the catechol hy- Ephedrine is a natural product isolated from
droxyls are esterified with pivalic acid. several species of ephedra plants, which were
Dipivefrin is used to treat open-angle glau- used for centuries in folk medicines in a vari-
coma through topical application to the eye ety of cultures worldwide (9). Ephedrine has
where the drug (4) is hydrolyzed to epineph- both direct activity on adrenoceptors and indi-
rine (2),which stimulates both a-and P-recep- rect activity, through causing release of nor-
tors, resulting in both decreased production epinephrine from adrenergic nerve terminals.
and increased outflow of aqueous humor, Ephedrine is widely used as a nonprescription
which in turn lowers intraocular pressure. bronchodilator. It has also been used as a va-
Amphetamine (3) is orally active and, sopressor and cardiac stimulant. Lacking phe-
through an indirect mechanism, causes a gen- nolic hydroxyls, ephedrine crosses the blood-
eral activation of the adrenergic nervous sys- brain barrier far better than does epinephrine.
tem. Unlike (1)and (2), amphetamine readily Because of its ability to penetrate the CNS,
crosses the blood-brain barrier to activate a ephedrine has been used as a stimulant and
number of adrenergic pathways in the central exhibits side effects related to its action in the
nervous system (CNS). Amphetamine's CNS brain such as insomnia, irritability, and anxi-
activity is the basis of its clinical utility in ety. It suppresses appetite and in high doses
treating attention-deficit disorder, narco- can cause euphoria or even hallucinations. In
lepsy, and use as an anorexiant. These thera- the United States the purified chemical ephed-
peutic areas are treated elsewhere in this rine is considered a drug and regulated by the
volume. FDA. However, the dried plant material ma
Ephedrine erythro-(5) and pseudoephed- huang is considered by law to be a dietary sup-
rine threo-(5) are diastereomers with ephed- plement, and not subject to FDA regulation.
rine, a racemic mixture of the R,S and S,R As a result there are a large number of ma
stereoisomers, and pseudoephedrine, a race- huang-containing herbal remedies and "nu-
2 Clinical Applications 11

Table 1.5 Aryloxypropanolamines (Structures 45-59)

Compound ARYL R Receptor Selectivity"
12 Adrenergics and Adrenergic-Blocking Agents

Table 1.5 (Continued)

Compound ARYL R Receptor Selectivitya

Plt Pz

triceuticals" on the market whose active in- 2.1.2 Applications of a,-Agonists. All se-
gredient is the adrenergic agonist ephedrine. lective a,-agonists are vasoconstrictors, which
Pseudoephedrine, the threo diastereomer, has is the basis of their therapeutic activity. The
virtually no direct activity on adrenergic re- sole use of levonordefrin (7)is in formulations
ceptors but acts by causing the release of nor- with parenteral local anesthetics employed in
epinephrine from nerve terminals, which in dentistry. Vasoconstriction induced by the
turn constricts blood vessels. Although it too a-agonist activity of (7) helps retain the local
crosses the blood-brain barrier, pseudoephed- anesthetic near the site of injection and pro-
rine's lack of direct activity affords fewer CNS longs the duration of anesthetic activity. Met-
side effects than does ephedrine. Pseudo- araminol (8) and methoxamine (9) are both
ephedrine is widely used as a nasal deconges- parenteral vasopressors selective for a-recep-
tant and is an ingredient in many nonprescrip- tors and so have few cardiac stimulatory prop-
tion cold remedies. erties. Because they are not substrates for
Mephentermine (8) is another general ad- COMT, their duration of action is significantly
renergic agonist with both direct and indirect longer than that of norepinephrine, but their
activity. Mephentermine's therapeutic utility primary use is limited to treating hypotension
is as a parenteral vasopressor used to treat during surgery or shock. Methoxamine is also
hypotension induced by spinal anesthesia or used in treating supraventricular tachycardia.
other drugs. Midodrine (10) is an orally active glycine-
2 Clinical Applications

Table 1.6 Miscellaneous AdrenergiclAntiadrenergics(Structures 60-62)

Compound Structure Pharmacological Activity
(60) Antiadrenergic

CH302C =-
(61) N-N


amide prodrug, hydrolyzed in vivo to (63), an severe hypotension or shock but is much
analog of methoxamine, and a vasoconstrictor. more widely employed as a nonprescription
Midodrine is used to treat orthostatic hypo- nasal decongestant in both oral and topical
tension. preparations.
The imidazolines naphazoline (29), oxy-
metazoline (301,tetrahydozoline (31),and xy-
lometazoline (32) are all selective a,-agonists,
widely employed as vasoconstrictors in topical
nonprescription drugs for treating nasal con-
gestion or bloodshot eyes. Naphazoline and
oxymetazoline are employed in both nasal de-
congestants and ophthalmic preparations,
whereas tetrahydrozoline is currently mar-
keted only for ophthalmic use and xylometa-
zoline only as a nasal decongestant.

2.1.3 Applications of a,-Agonists. Arnino-

imidazolines apraclonidine (33) and bri-
monidine (34) are selective a,-agonists em-
ployed topically in the treatment of glaucoma.
Stimulation of a,-receptors in the eye reduces
production of aqueous humor and enhances
outflow of aqueous humor, thus reducing in-
Phenylephrine (111, also a selective a-ago- traocular pressure. Brimonidine is substan-
nist, may be administered parenterally for tially more selective for a,-receptors over a,-
Adrenergics and Adrenergic-Blocking Agents

receptors than is apraclonidine. Although both formoterol (15), isoetharine (16),isoprotere-

are applied topically to the eye, measurable no1 (17), levalbuterol [R-(-)-(1311, metapro-
quantities of these drugs are detectable in terenol (18), pirbuterol (191, salmeterol (21),
plasma, so caution must be employed when and terbutaline (22) are used primarily as
the patient is also taking cardiovascular bronchodilators in asthma and other constric-
agents. Structurally related aminoimidazoline tive pulmonary conditions. Isoproterenol(17)
clonidine (35) is a selective a2-agonist taken is a general P-agonist; and the cardiac stimu-
orally for treatment of hypertension. The anti- lation caused by its &-activity and its lack of
hypertensive actions of clonidine are mediated oral activity attributed to first-pass metabo-
through stimulation of a,-adrenoceptors lism of the catechol ring have led to dimin-
within the CNS, resulting in an overall decrease ished use in favor of selective p,-agonists.
in peripheral sympathetic tone. Guanabenz (36) Noncatechol-selective P2-agonists,such as al-
and guanfacine (37) are ring-opened analogs of buterol (13), metaproterenol (181, and ter-
(351, acting by the same mechanism and em- butaline (22), are available in oral dosage
ployed as centrally acting antihypertensives. forms as well as in inhalers. All have similar
Methyldopa (12) is another antihyperten- activities and durations of action. Pirbuterol
sive agent acting as an a,-agonist in the CNS (19) is an analog of albuterol, in which the
through its metabolite, a-methyl-norepineph- benzene ring has been replaced by a pyridine
rine (65). Methyldopa [the drug is the L-(5')- ring. Similar to albuterol, (19) is a selective
stereoisomer] is decarboxylated to a-methyl- P2-agonist,currently available only for admin-
dopamine (64) followed by stereospecific istration by inhalation. Bitolterol(14) is a pro-
p-hydroxylation to the (1R,2S) stereoisomer drug, in which the catechol hydroxyl groups
of a-methylnorepinephrine (65). This stereo- have been converted to 4-methylbenzoic acid
isomer is an a,-agonist that, like clonidine, esters, providing increased lipid solubility and
guanabenz, and guanfacine, causes a decrease prolonged duration of action. Bitolterol is ad-
in sympathetic output from the CNS. ministered by inhalation, and the ester groups
are hydrolyzed by esterases to liberate the ac-
tive catechol drug (66), which is subject to me-
tabolism by COMT, although the duration of
action of a single dose of the prodrug is up to
8 h, permitting less frequent administration
and greater convenience to the patient. More
recently developed selective &-agonist bron-
chodilators are formoterol(l5) and salmeterol
(21),which have durations of action of 12 h or
more. Terbutaline (221, in addition to its use
as a bronchodilator, has also been used for
halting the contractions of premature labor.
Ritodrine (20) is a selective P2-agonist that is
used exclusively for relaxing uterine muscle
and inhibiting the contractions of premature

2.1.5 Applications of Antiadrenergics. Gua-

nadrel (38) and guanethidine (39) are orally
active antihypertensives, which are taken up
into adrenergic neurons, where they bind to
the storage vesicles and prevent release of
neurotransmitter in response to a neuronal
2.1.4 Applications of fi-Agonists. Most of impulse, which results in generalized decrease
the /3-selective adrenergic agonists, albuterol in sympathetic tone. These drugs are available
(13; salbutamol in Europe), bitolterol (141, but seldom used.
2 Clinical Applications

in pheochromocytoma tumors, it is not useful

for treating essential hypertension.

2.1.6 Applications of Nonselective a-An-

tagonists. Because antagonism of a,-adreno-
ceptors in the peripheral vascular smooth
muscle leads to vasodilation and a decrease in
blood pressure attributed to a lowering of pe-
ripheral resistance, alpha-blockers have been
employed as antihypertensives for decades.
However, nonselective a-blockers such as phe-
noxybenzamine (62), phentolamine (40), and
tolazoline can also increase sympathetic out-
put through blockade of inhibitory presynap-
tic a,-adrenoceptors, resulting in an increase
in circulating norepinephrine, which causes
reflex tachycardia. Thus the use of these
agents in treating most forms of hypertension
has been discontinued and replaced by use of
selective a,-antagonists discussed below. Cur-
Reserpine (60)is an old and historically im- rent clinical use of the nonselective agents
portant drug that affects the storage and re- (40), (41), and (62) is primarily treatment of
lease of norepinephrine. Reserpine is one of hypertension induced by pheochromocytoma,
several indole alkaloids isolated from the roots a tumor of the adrenal medulla, which se-
of Rauwolfia serpentina, a plant whose roots cretes large amounts of epinephrine and nor-
were used in India for centuries as a remedy epinephrine into the circulation. Dapiprazole
for snakebites and as a sedative. Reserpine (61) is an ophthalmic nonselective a-antago-
acts to deplete the adrenergic neurons of their nist applied topically to reverse mydriasis in-
stores of norepinephrine by inhibiting the ac- duced by other drugs and is not used to treat
tive transport Mg-ATPase responsible for se- hypertension.
questering norepinephrine and dopamine
within the storage vesicles. Monoamine oxi- 2.1.7 Applications of Selective a,-Antago-
dase (MAO) destroys the norepinephrine and nists. Quinazoline-selective a,-blockers dox-
azosin (42), prazosin (43), and terazosin (44)
dopamine that are not sequestered in vesicles.
have replaced the nonselective a-antagonists
As a result the storage vesicles contain little
in clinical use as antihypertensives. Their abil-
neurotransmitter; adrenergic transmission is
ity to dilate peripheral vasculature has also
dramatically inhibited; and sympathetic tone made these drugs useful in treating Raynaud's
is decreased, thus leading to vasodilation. syndrome. The a,-selective agents have a fa-
Agents with fewer side effects have largely re- vorable effect on lipid profiles and decrease
placed reserpine in clinical use. low density lipoproteins (LDL) and triglycer-
Metyrosine (23, a-methyl-L-tyrosine), a ides, and increase high density lipoproteins
norepinephrine biosynthesis inhibitor, is in (HDL).
limited clinical use to help control hyperten- Contraction of the smooth muscle of the
sive episodes and other symptoms of catechol- prostate gland, prostatic urethra, and bladder
amine overproduction in patients with the neck is also mediated by a,-adrenoceptors,
rare adrenal tumor pheochromocytoma (10). with a,, being predominant, and blockade of
Metyrosine, a competitive inhibitor of ty- these receptors relaxes the tissue. For this rea-
rosine hydroxylase, inhibits the production of son the quinazoline a,-antagonists doxazosin
catecholamines by the tumor. Although mety- (42), prazosin ( 4 9 , and terazosin (44) have
rosine is useful in treating hypertension also found use in treatment of benign pros-
caused by excess catecholamine biosynthesis tatic hyperplasia (BPH). However, prazosin,
Adrenergics and Adrenergic-Blocking Agents

doxazosin, and terazosin show no significant 2.1.9 Applications of dj3-Antagonists. Car-

selectivity for any of the three known a,-adre- vedilol (591, an aryloxypropanolamine, has
noceptor subtypes, a,,, a,,, and a,, (11).The both a- and p-antagonist properties and is
structurally unrelated phenylethylamine a,- used both as an antihypertensive and to treat
antagonist tamsulosin (24) is many fold more cardiac failure. Both enantiomers have selec-
selective for a,,-receptors than for the other tive a,-antagonist properties but most of the
a,-adrencoceptors. Tamsulosin is employed p-antagonism is attributable to the S-(-)iso-
only for treatment of BPH, given that it has mer. Labetalol(26) is also an antihypertensive
little effect on the a,,- and a,,-adrenoceptors, with both selective a,-antagonist properties
which predominate in the vascular bed (12) and nonselective p-antagonism. Labetalol is
and have little effect on blood pressure (13).
an older drug than carvedilol and is not as
potent as carvedilol, particularly as a p-antag-
2.1.8 Applications of &Antagonists. p-An-
tagonists are among the most widely employed
antihypertensives and are also considered the 2.1 .I 0 Applications of Agonists/Antago-
nists. Dobutamine (27) is a positive inotropic
first-line treatment for glaucoma. There are
agent administered intravenously for conges-
16 p-blockers listed in Table 1.1 and 15 of
tive heart failure. The (+)-isomer has both a
them are in the chemical class of aryloxypro-
and p agonist effects, whereas the (-)-isomer
panolamines. Only sotalol(25) is a phenyleth- is an a-antagonist but a P-agonist like the en-
ylamine. Acebutolol (451, atenolol (46), biso- antiomer. The p-stirnulatory effects predomi-
pro101 (481, metoprolol (53), nadolol (54), nate as the a-effects cancel. As a catechol it
penbutolol (551, pindolol (561, and proprano- has no oral activity and even given intrave-
lo1 (57)are used to treat hypertension but not nously has a half-life of only 2 min. Isoxsu-
glaucoma. Betaxolol (471, carte0101 (49), and prine (28) is an agent with a-antagonist and
timolol(58)are used both systemically to treat P-agonist properties, which has been used for
hypertension and topically to treat glaucoma. peripheral and cerebral vascular insufficiency
Levobetaxolol [S-(-)-(47)], levobunolol (51), and for inhibition of premature labor. Isoxsu-
and metipranolol (52) are employed only in prine is seldom used any more.
treating glaucoma. Betaxolol (racemic 47) is
available in both oral and ophthalmic dosage 2.2 Absorption, Distribution, Metabolism,
forms for treating hypertension and glau- and Elimination
coma, respectively, but levobetaxolol, the en-
Because of the large numbers of chemicals act-
antiomerically pure S-(-)-stereoisomer is cur- ing as either adrenergics or adrenergic-block-
rently available only in an ophthalmic dosage ing drugs, only representative examples will
form. Esmolol (50) is a very short acting be given and limited to metabolites identified
p-blocker administered intravenously for in humans. Because drugs with similar struc-
acute control of hypertension or certain su- tures are often metabolized by similar routes,
praventricular arrhythmias during surgery. the examples chosen are representative of
Sotalol(25)is a nonselective p-blocker used to each structural class. Although it contains no
treat ventricular and supraventricular ar- structural details of metabolic pathways,
rhythmias not employed as an antihyperten- Drug Facts and Comparisons (14) is an out-
sive or antiglaucoma agent. P-Antagonists standing comprehensive compilation of phar-
must be used with caution in patients with macokinetic parameters such as absorption,
asthma and other reactive pulmonary diseases duration of action, and routes of elimination
because blockade of P,-adrenoceptors may ex- for drugs approved by the FDA for use in the
acerbate the lung condition. Even the agents United States.
listed as being &-selective have some level of
p,-blocking activity at higher therapeutic 2.2.1 Metabolism of Representative Phenyl-
doses. Betaxolol is the most p,-selective of the ethylamines. Norepinephrine (1) and epi-
currently available agents. nephrine (2) are both substrates for MAO,
2 Clinical Applications

which oxidatively deaminates the side chain of shown. Any catechol-containing drug will also
either to form the same product DOPGAL likely be subject to metabolism by COMT.
(67), and for catechol-0-methyltransferase Ephedrine (51, a close structural analog of
(COMT), which methylates the 3'-phenolic (2), having no substituents on the phenyl ring,
OH of each to form (68). Metabolite (68) is is well absorbed after an oral dose and over
subsequently oxidized by MA0 to form alde- half the dose is eliminated unchanged in the
hyde (69), and aldehyde (68) may be methyl- urine. The remainder of the dose is largely
ated by COMT to also form (69). This alde- desmethylephedrine (72), deamination prod-
hyde may then be either oxidized by aldehyde uct (73), and small amounts of benzoic acid
dehydrogenase (AD) to (70) or reduced by al- and its conjugates (16). No aromatic ring-hy-
dehyde reductase to alcohol (71). Alternate droxylation products were detected. This is in
routes to (70) and (71) from (67) are also marked contrast to the case with amphet-
shown. Several of these metabolites are ex- amine (3), in which ring-hydroxylated prod-
creted in the urine as sulfate and glucuronide ucts are major metabolites.
conjugates (15).As previously mentioned, nei- Albuterol(13) is not subject to metabolism
ther (1)nor (2) is orally active because of ex- by COMT and is orally active but does have a
tensive first-pass metabolism by COMT, and 4'- OH group subject to conjugation. The ma-
both have short durations of action because of jor metabolite of albuterol (13) is the 4'-0-
rapid metabolic deactivation by the routes sulfate (74) (17). The sulfation reaction is ste-

c H 3 0CHO~ H" (68)

HO \
Adrenergics and Adrenergic-Blocking Agents

reoselective for the active R-(-)-isomer (18-

201, resulting in higher plasma levels of the
less active S-(+)-isomer after oral administra- urine and the remainder oxidized by the liver
tion or swallowing of inhaled dosages. on both the phenyl ring and imidazoline ring
Tamsulosin (24)is metabolized by CYP3A4 to (771, (781, and (79).Oxidation of the imida-
to both the phenolic oxidation product (75) zoline ring presumably leads to the ring-
and deaminated metabolite (76) and their con- opened derivatives (80) and (81). All metabo-
jugation products (21-23). The other products lites are inactive but do not appear to be
generated from the remainder of the drug further conjugated.
molecule during formation of (76) were not In contrast, less than 2% of guanabenz
explicitly identified. Tamsulosin is well ab- (36), a ring-opened analog of (351, is excreted
sorbed orally and extensively metabolized. unchanged in the urine (24). The major me-
Less than 10% excreted unchanged in urine. tabolite (35%) is the 4-hydroqdated com-
pound (82) and its conjugates, whereas guana-
2.2.2 Metabolism of Representative Imida- benz-N-glucuronide accounts for about 6%.
zolines and Cuanidines. In humans, clonidine Also identified were 2,6-dichlorobenzyl alco-
(35)is excreted about 50% unchanged in the hol (83) (as conjugates) and the 2-isomer of
2 Clinical Applications

with little or no first-pass metabolism, and

about 38% of administered terazosin is elimi-
nated unchanged in urine and feces. The re-
mainder is metabolized by hydrolysis of the
amide bond to afford (84) and by O-demethyl-
ation to form the 6- and 7-0-demethyl metab-
olites (85)and (86), respectively (25). Diamine
(87) has also been identified as a minor metab-
olite of terazosin, probably arising from oxida-
tion and hydrolysis of the piperazine ring, al-
though the intermediate products have not
been identified.
Doxazosin (42) is well absorbed, with 60%
bioavailability, but only about 5% is ex-
creted unchanged. The major routes of me-
tabolism are, like terazosin, 6- and 7-0-
demethylation t o afford (88) and (891,
respectively (26). Hydroxylation a t 6' and 7',
to form (90) and (91), forms the other two
identified metabolites.

2.2.4 Metabolism of Representative Aryl-

oxypropanolamines. Propranolol ( 5 7 ) , the
first successful p-blocker, is also the most li-
pophilic, with an octanol/water partition coef-
ficient of 20.2 (27), and is extensively metabo-
lized. At least 20 metabolites of propranolol
have been demonstrated (28), only a few of
which are shown. The 4'-hydroxy metabolite
guanabenz. About 15 other trace metabolites (92) is equipotent with the parent compound
were detected by chromatography but not (29). CYP2D6 is responsible for the 4'-hy-
identified. droxylation and CYPlA2 for oxidative re-
moval of the isopropyl group from the nitro-
2.2.3 Metabolism of Representative Quina- gen to form (93) (30). The metabolites as well
zolines. Terazosin (46) is completely absorbed, as the parent drug are extensively conjugated

+ conjugates + Z-isomer of (36)

20 Adrenergics and Adrenergic-Blocking Agents
3 Physiology and Pharmacology 21

OH 0/\f\cH20H
'OZH+ many conjugates

@ O"
/ / / /

as sulfates and glucuronides. The high lipophi-

licity of propranolol provides ready passage
across the blood-brain barrier and leads to the
significant CNS effects of propranolol(27).
On the other hand, atenolol (461, with an
octanollbuffer partition coefficient of 0.02
(27),does not cross the blood-brain barrier to
any significant extent and is eliminated al-
most entirely as the unchanged parent drug in
the urine and feces. Very small amounts of
hydroxylated metabolite (94) and its conju-
gates have been identified (31), but well over
90% of atenolol is eliminated unchanged.
Metoprolol(53) is cleared principally by he-
patic metabolism and is only 50% bioavailable
because of extensive first-pass metabolism.
The major metabolite (65%) is the carboxylic
acid (951, produced by CYP2D6 O-demethyl-
ation followed by further oxidation (32-34).
Benzylic oxidation CYP2D6 forms an active
- + conjugates
metabolite (961, which retains beta-blocking
activity (35). The N-dealkylated product is a
minor metabolite.


normally activated by the neurotransmitter
norepinephrine (1, noradrenaline), or they
The physiology and pharmacology of adrener-
may act on the neurons that release the neu-
gic and adrenergic-blocking drugs are well
rotransmitter. The term adrenergic stems
covered in standard pharmacology textbooks
from the discovery early in the twentieth cen-
tury that administration of the adrenal med-
ullar hormone adrenaline (epinephrine) had
3.1 Physiological Significance
specific effects on selected organs and tissues
Adrenergic and adrenergic-blocking drugs act similar to the effects produced by stimulation
on effector cells through receptors that are of the sympathetic nervous system, which was
Adrenergics and Adrenergic-Blocking Agents

(96) active

originally defined anatomically (38).Today of the axon near the junction with the effector
the terms adrenergic nervous system and sym- cell. The amino acid L-tyrosine(97)is actively
pathetic nervous system are generally used in- transported into the neuron cell (411,where
terchangeably. The sympathetic nervous sys- the cytoplasmic enzyme tyrosine hydroxylase
tem is a division of the autonomic nervous (tyrosine-3-monooxygenase) oxidizes the 3'-
system, which innervates organs such as the position to form the catechol-amino-acid L-
heart, lungs, blood vessels, glands, and smooth dopa (98) in the rate-limiting step in norepi-
muscle in various tissues and regulates func- . nephrine biosynthesis (42). L-Dopa is
tions not normally under voluntary control. decarboxylated to dopamine(99)by aromatic-
The effects of the sympathetic stimulation on L-amino acid decarboxylase, another cytoplas-
a few organs and tissues of particular rele- mic enzyme. Aromatic-L-aminoacid decarboxyl-
vance to current pharmaceutical interven- ase is more commonly known as dopa
tions are shown in Table 1.7 (39,40). Excellent decarboxylase. Doparnine is then taken up by
overviews of the adrenergic nervous system active transport into storage vesicles or granules
and its role in control of human physiology are located near the terminus of the adrenergic neu-
provided in Katzung (39) and Hoffman and ron. Within these vesicles, the enzyme dopa-
Palmer(40). mine P-hydroxylase stereospecifically intro-
duces a hydroxyl group in the R absolute
3.2 Biosynthesis, Storage, and Release
configuration on the carbon atom beta to the
of Norepinephrine
amino group to generate the neurotransmitter
Biosynthesis of norepinephrine takes place norepinephrine (1).Norepinephrine is stored in
within adrenergic neurons near the terminus the vesicles in a 4:l complex, with adenosine
3 Physiology and Pharmacology 23

Table 1.7 Selected Tissue Response to Adrenergic Stimulation

Tissue Principal Adrenergic Receptor Effect
Heart PI (minor Pz, P3) Increased rate and force
Blood vessels
Skin, mucosa, visera a1 Constriction
Skeletal muscle Pz Dilation
Renal a1 Constriction
Lungs (bronchial muscle) Pz Relaxation
Radial muscle, iris a1 Contraction (pupilary dilation)
Ciliary muscle Pz Relaxation
Uterus (pregnant) Pz Relaxation
Liver a,, Pz Glycogenolysis, gluconeogenesis
Fat cells P3 Lipolysis
Renin release PI Increased renin secretion
minor a1 Decreased renin secretion

triphosphate (ATP)in such quantities that each nephrine biosynthesis, release, and fate is
vesicle in a peripheral adrenergic neuron con- given in Fig. 1.1.After release, norepinephrine
tains between 6000 and 15,000 molecules of nor- diffuses through the intercellular space to
epinephrine (43). The pathway for epinephrine bind reversibly to adrenergic receptors (alpha
(2) biosynthesis in the adrenal medulla is the or beta) on the effector cell, triggering a bio-
same, with the additional step of conversion of chemical cascade that results in a physiologic
(1)to (2) by phenylethanolamine-N-methyl- response by the effector cell. In addition to the
transferase. receptors on effector cells, there are also adre-
Norepinephrine remains in the vesicles un- noreceptors that respond to norepinephrine
til it is released into the synapse during signal (a2-receptors) or epinephrine (P2-receptors)
transduction. A wave of depolarization reach- on the presynaptic neuron, which modulate
ing the terminus of an adrenergic neuron trig- the release of additional neurotransmitter
gers the transient opening of voltage-depen- into the synapse. Activation of presynaptic a,-
dent calcium channels, causing an influx of adrenoceptors by (1)inhibits the release of ad-
calcium ions. This influx of calcium ions trig- ditional (I),whereas stimulation of presynap-
gers fusion of the storage vesicles with the tic P,-adrenoceptors by (2) enhances the
neuronal cell membrane, spilling the norepi- release of (I),thus increasing overall sympa-
nephrine and other contents of the vesicles thetic activation. Removal of norepinephrine
into the synapse through exocytosis. A sum- from the synapse is accomplished by two
mary view of the events involved in norepi- mechanisms, reuptake and metabolism, to in-

Adrenergic neuron Effector cell

enhancement of
NE release

Storage vesicle

and Ca++influx
rn - biochemical
t 2 NE


DOPGAL, 67 4 MA0
t Uotake-1
Tyrosine metabolism

Figure 1.1. Diagram of synapse between an adrenergic neuron and its effector cell. NE, norepineph-
rine; aR, a-adrenoceptor; pR, P-adrenoceptor.
3 Physiology and Pharmacology

active compounds. The most important of ceptors, except that linkage through a G-pro-
these mechanisms is transmitter recycling tein (G,) leads to inhibition of adenylyl cyclase
through active transport uptake into the pre- instead of activation.
synaptic neuron. This process, called up- The a,-adrenoreceptor, on the other hand,
take-1, is efficient and, in some tissues, up to is linked through yet another G-protein to a
95% of released norepinephrine is removed complex series of events involving hydrolysis
from the synapse by this mechanism (44).Part of polyphosphatidylinositol (46). The first
of the norepinephrine taken into the presyn- event set in motion by activation of the a,-
aptic neuron by uptake-1 is metabolized by receptor is activation of the enzyme phospho-
MA0 through the same processes discussed lipase C, which catalyzes the hydrolysis of
earlier under norepinephrine metabolism, but phosphatidylinositol-4,5-biphosphate(PIP,).
most is sequestered in the storage vesicles to This hydrolysis yields two products, each of
be used again as neurotransmitter. This up- which has biologic activity as second messen-
take mechanism is not specific for (1)and a gers of the a,-receptor. These are 1,2-diacyl-
number of drugs are substrates for the uptake glycerol (DAG) and inositol-1,4,5-triphos-
mechanism and others inhibit reuptake, lead- phate (IP,). IP, causes the release of calcium
ing to increased adrenergic stimulation. A less ions from intracellular storage sites in the en-
efficient uptake process, uptakeS, operates in doplasmic reticulum, resulting in an increase
a variety of other cell types but only in the in free intracellular calcium levels. Increased
presence of high concentrations of norepi- free intracellular calcium is correlated with
nephrine. That portion of released norepi- smooth muscle contraction. DAG activates cy-
nephrine that escapes uptake-1 diffuses out of tosolic protein kinase C, which may induce
the synapse and is metabolized in extraneuro- slowly developing contractions of vascular
nal sites by COMT. MA0 present at extraneu- smooth muscle. The end result of a complex
ronal sites, principally the liver and blood series of protein interactions triggered by ag-
platelets, also metabolizes norepinephrine. onist binding to the a,-adrenoceptor includes
increased intracellular free calcium, which
3.3 Effector Mechanisms
leads to smooth muscle contraction. Because
of Adrenergic Receptors
smooth muscles of the wall of the peripheral
Adrenoceptors are proteins embedded in the vascular bed are innervated by a,-receptors,
cell membrane that are coupled through a G- stimulation leads to vascular constriction and
protein to effector mechanisms that translate
an increase in blood pressure.
conformational changes caused by activation 3.4 Characterization of Adrenergic
of the receptor into a biochemical event within
Receptor Subtypes
the cell. All of the P-adrenoceptors are coupled
through specific G-proteins (G,) to the activa- The discovery of subclasses of adrenergic re-
tion of adenylyl cyclase (45). When the recep- ceptors and the ability of relatively small mol-
tor is stimulated by an agonist, adenylyl cy- ecule drugs to stimulate differentially or block
clase is activated to catalyze conversion of these receptors represented a major advance
ATP to cyclic-adenosine monophosphate in several areas of pharmacotherapeutics. An
(CAMP),which diffuses through the cell for at excellent review of the development of adreno-
least short distances to modulate biochemical ceptor classifications is available in Hiebel et
events remote from the synaptic cleft. Modu- al. (47).
lation of biochemical events by CAMPincludes The adrenoceptors, both alpha and beta,
a phosphorylation cascade of other proteins. are members of a receptor superfamily of
CAMPis rapidly deactivated by hydrolysis of membrane-spanning proteins, including mus-
the phosphodiester bond by the enzyme phos- carine, serotonin, and dopamine receptors,
phodiesterase. The a,-receptor may use more that are coupled to intracellular GTP-binding
than one effector system, depending on the proteins (G-proteins), which determine the
location of the receptor; however, to date the cellular response to receptor activation (48).

best understood effector system of the a,-re- All G-protein-coupled receptors exhibit a
ceptor appears to be similar to that of the p-re- common motif of a single polypeptide chain
Adrenergics and Adrenergic-Blocking Agents

that is looped back and forth through the cell including the actual peptide sequence and
membrane seven times, with an extracellular length. Each of the adrenoceptors is encoded
N-terminus and intracellular C-terminus. on a distinct gene, and this information was
One of the most thoroughly studied of these considered crucial to the proof that each adre-
receptors is the human P,-adrenoreceptor noreceptor is indeed distinct, although re-
(49). The seven transmembrane domains, lated. The amino acids that make up the seven
TMD1-TMD7, are composed primarily of li- transmembrane regions are highly conserved
pophilic amino acids arranged in a-helices among the various adrenoreceptors, but the
connected by regions of hydrophilic amino ac- hydrophilic portions are quite variable. The
ids. The hydrophilic regions form loops on the largest differences occur in the third intracel-
intracellular and extracellular faces of the lular loop connecting TMD5 and TMD6, which
membrane. In all of the adrenoceptors the ag- is the site of linkage between the receptor and
onistlantagonist recognition site is located its associated G-protein. Sequences and bind-
within the membrane-bound portion of the re- ing specificities have been reported for numer-
ceptor. This binding site is within a pocket ous a- and P-adrenoceptor subtypes (47, 53-
formed by the membrane-spanning regions of 56). For purposes of drug design and
the peptide. All of the adrenoceptors are cou- therapeutic targeting, the most critical recep-
pled to their G-protein through reversible tors are the a,, on prostate smooth muscle,
binding interactions with the third intracellu- a,, on vascular smooth muscle and in the kid-
lar loop of the receptor protein. ney, a, in the CNS, P, in heart, P, in bronchial
Binding studies with selectively mutated smooth muscle, and p, in adipose tissue.
P,-receptors have provided strong evidence
for binding interactions between agonist func-
tional groups and specific residues in the 4 HISTORY
transmembrane domains of adrenoceptors
(50-52). Such studies indicate that Asp,,, in In 1895 Oliver and Schafer reported (57) that
transmembrane domain 3 (TMD3) of the P,- adrenal gland extracts caused vasoconstric-
receptor is the acidic residue that forms a tion and dramatic increases in blood pressure.
bond, presumably ionic or a salt bridge, with Shortly thereafter various preparations of
the positively charged amino group of cate- crude adrenal extracts were being marketed
cholamine agonists. An aspartic acid residue is largely to staunch bleeding from cuts and
also found in a comparable position in all of abrasions. In 1899 Abel reported (58) isolation
the other adrenoceptors as well as other of a partially purified sample of the active con-
known G-protein-coupled receptors that bind stituent (2), which he named epinephrine.
substrates having positively charged nitro- Shortly thereafter von Fiirth (59)employed an
gens in their structures. Elegant studies with alternative procedure to isolate another im-
mutated receptors and analogs of isoprotere- pure sample of (2), which he named suprare-
no1 demonstrated that Ser,,, and Ser,,, of nin, claiming it to be a different substance
TMD5 are the residues that form hydrogen than that isolated by Abel. The pure hormone
bonds with the catechol hydroxyls of &-ago- (2) was finally obtained in 1901 by both Taka-
nists. Furthermore, the evidence indicates mine (60) and Aldrich (61). Takamine gave (2)
that Ser,,, interacts with the meta hydroxyl yet a third name, adrenalin. Although the
group of the ligand, whereas Ser,,, interacts chemical structure was still not definitively
specifically with the para hydroxyl group. known, a pure preparation of (2) was first
Serine residues are found in corresponding po- marketed by Parke, Davis & Co. under the
sitions in the fifth transmembrane domain of trade name Adrenaline (62, 63). Adrenaline
the other known adrenoceptors. Evidence in- eventually became the generic name employed
dicates that the phenylalanine residue of outside the United States, whereas epineph-
TMD6 is also involved in ligand-receptor rine became the U.S. approved name. By 1903
bonding with the catechol ring. Structural dif- Pauly (64) had demonstrated that "adrena-
ferences exist among the various adrenocep- line" was levorotatory and proposed two pos-
tors with regard to their primary structure, sible structures consistent with the available
4 History

data. The structure of racemic (2) was conclu- chlorines, was discovered to be a P-antagonist
sively proved through nearly simultaneous that blocked the effects of sympathomimetic
synthesis by Stolz at Farbwerke Hoechst (65) amines on bronchodilation, uterine relax-
and Dakin at the University of Leeds (66), but ation, and heart stimulation (75). Although
it had only one half the activity of the natural DCI had no clinical utility, replacement of the
levorotatory isomer (67). The racemate was 3,4-dichlorosubstituents with a carbon bridge
resolved by Flacher in 1908 (68). to form a naphthylethanolamine derivative
The earliest major clinical application of (2) did afford a clinical candidate, pronethalol
was the report in 1900 (69) of the utility of (1011, introduced in 1962 only to be with-
injected adrenal extracts in treating asthma drawn in 1963 because of tumor induction in
attacks, followed in 1903 by a report (70)of the animal tests.
use of purified (2) for the same purpose. In-
jected epinephrine rapidly became the stan-
dard therapy for treatment of acute asthma
attacks. A nasal spray containing epinephrine
was available by 1911 and administration
through an inhaler was reported in 1929. Also,
early in the 1900s Hoechst employed the vaso-
constrictor properties of epinephrine to pro-
long the duration of action of their newly de-
veloped local anesthetic procaine (63).
It had been recognized early on (71) that
there were similarities between the effects of
administration adrenal gland- extracts and
stimulation of the sympathetic nervous sys-
tem. Elliot (72) suggested that adrenaline
might be released by sympathetic nerve stim-
ulation and over the years the term adrenergic
nerves became effectively synonymous with
sympathetic nerves. In 1910 Barger and Dale Shortly thereafter, a major innovation was
(73) reported a detailed structure-activity re- introduced when it was discovered that an
lationship study of epinephrine analogs and oxymethylene bridge, OCH,, could be intro-
introduced the term sympathomimetic for duced into the arylethanolamine structure of
chemicals that mimicked the effects of sympa- pronethalol to afford propranolol(57), an ary-
thetic nerve stimulation, but they also noted loxypropanolamine and the first clinically suc-
some important differences between the ef- cessful P-blocker.
fects of administered adrenaline and stimula- To clarify some of the puzzling differential
tion of sympathetic nerves. It was not until effects of sympathomimetic drugs on various
1946 that von Euler demonstrated that the tissues, in 1948 Ahlquist (76) introduced the
actual neurotransmitter released at the termi- concept of two distinct types of adrenergic re-
nus of sympathetic neurons was norepineph- ceptors as defined by their responses to (11,
rine (1)rather than epinephrine (2) (74). In (2), and (17), which he called alpha receptors
1947 compound (17), the N-isopropyl analog and beta receptors. Alpha receptors were de-
of (1)and (21, was reported to possess bron- fined as those that responded in rank order of
chodilating effects similar to those of (2) but agonist potency as (2) > (1)>> (17). Beta re-
lacking its dangerous pressor effects. In 1951 ceptors were defined as those responding in
(17) was introduced into clinical use as isopro- potency order of (17) > (2) > (1).Subse-
terenol (isoprenaline) and became the drug of quently, P-receptors were further divided into
choice for treating asthma for two decades. PI-receptors, located primarily in cardiac tis-
In the 1950s, dichloroisoprotereno1 (DCI, sue, and &-adrenoceptors, located in smooth
loo), a derivative of isoproterenol, in which muscle and other tissues, given that (1)and
the catechol hydroxyls had been replaced by (2) are approximately equipotent at cardiac
Adrenergics and Adrenergic-Blocking Agents

P-receptors, although (2) is 10 to 50 times ture of the other substituents determines re-
more potent than (1)at most smooth muscle ceptor selectivity and duration of action.
P-receptors (77). Alpha receptors were also
subdivided into a, (postsynaptic) and a, (pre- 5.1.1 R' Substitution on the Amino Nitrogen.
synaptic) adrenoceptors (78). Development of As R1 is increased in size from hydrogen in
selective agonists and antagonists for these norepinephrine to methyl in epinephrine to
various adrenoceptors has been thoroughly re- isopropyl in isoproterenol, activity at a-recep-
viewed in Ruff010 et al. (79). tors decreases and activity at P-receptors in-
creases. Activity at both a- and P-receptors is
maximal when R1 is methyl as in epinephrine,
but a-agonist activity is dramatically de-
creased when R1 is larger than methyl and is
Comprehensive reviews of the structure-activ-
negligible when R1 is isopropyl as in (17), leav-
ity relationships (SAR) of agonists and antag-
ing only P-activity. Presumably, the P-recep-
onists of a-adrenoceptors (80) and P-adreno-
tor has a large lipophilic binding pocket adja-
ceptors (81) are available, which thoroughly
cent to the amine-binding aspartic acid
cover developments through the late 1980s.
residue, which is absent in the a-receptor. As
Only summaries of these structure-activity re-
R1 becomes larger than butyl, affinity for a,-
lationships are provided here.
receptors returns, but not intrinsic activity,
which means large lipophilic groups can afford
5.1 Phenylethylamine Agonists
compounds with a,-blocking activity [e.g.,
The structures of the phenylethylamine ad- tamsulosin (24) and labetalol (26)l. Tarnsulo-
renergic agonists were summarized in Table sin (24) is more selective for a,,, the a,-adre-
1.2. Agents of this type have been extensively noceptor subtype found in the prostate gland,
over those found in vascular tissue. In addi-
tion, the N-substituent can also provide selec-
tivity for different P-receptors, with a t-butyl
group affording selectivity for &-receptors.
For example, with all other features of the
molecules being constant, (66) [the active
metabolite of prodrug bitolterol (1411 is a se-
lective P,-agonist, whereas (17) is a general
P-agonist. When considering its use as a bron-
studied over the years since the discovery of chodilator, it must be recognized that a gen-
the naturally occurring prototypes, epineph- eral P-agonist such as (17) has undesirable
rine and norepinephrine, and the structural cardiac stimulatory properties (because of its
requirements, and tolerances for substitu- &-activity) that are greatly diminished in a
tions at each of the indicated positions have selective P,-agonist.
been well established and reviewed (79,82).In
5.1.2 RZ Substitution a to the Basic Nitro-
general, a primary or secondary aliphatic
gen, Carbon-2. Small alkyl groups, methyl or
amine separated by two carbons from a substi-
ethyl, may be present on the carbon adjacent
tuted benzene ring is minimally required for to the amino nitrogen. Such substitution
high agonist activity in this class. Tertiary or slows metabolism by MA0 but has little over-
quaternary amines have little activity. Be- all effect on duration of action of catechols be-
cause of the basic amino groups, pK, values cause they remain substrates for COMT. Re-
range from about 8.5 to 10, and all of these sistance to MA0 activity is more important
agents are highly positively charged at physi- in noncatechol indirect-acting phenylethyl-
ologic pH. Most agents in this class have a amines. An ethyl group in this position dimin-
hydroxyl group on C-1 of the side chain, P to ishes a-activity far more than P-activity, and is
the amine, as in epinephrine and norepineph- present in isoetharine (16). Substitution on
rine. Given these features in common, the na- this carbon introduces an asymmetric center,
5 Structure-Activity Relationships

producing pairs of diastereomers when an OH substituent does not affect the ability of the
group is present on C-1. These stereoisomers drug to bind to the a,-receptor but does affect
can have significantly different biologic and the ability of the molecule to activate the re-
chemical properties. For example, maximal ceptor; that is, the stereochemistry of the
direct activity in the stereoisomers of a-meth- methyl group affects intrinsic activity but not
ylnorepinephrine resides in the erythro ste- affinity. Because both stereoisomers are
reoisomer (65), with the (1R,2S) absolute con- p-agonists, with the (+)-isomer about 10
figuration (83), which is the active metabolite times as potent as the (-)-isomer, the net ef-
of the prodrug methyldopa (12) (84). The con- fect is p-stimulation. Dobutamine is used as a
figuration of C-2 has a great influence on re- cardiac stimulant after surgery or congestive
ceptor binding because the (1R,2R) diaste- heart failure. As a catechol, dobutamine is
reomer of a-methylnorepinephrine has readily metabolized by COMT and has a short
primarily indirect activity, even though the ab- duration of action with no oral activity.
solute configuration of the hydroxyl-bearing C-1
is the same as that in norepinephrine. In 5.1.4 R4 Substitution on the Aromatic
addition, with respect to a-activity, this addi- Ring. The natural 3',4'-dihydroxy substituted
tional methyl group also makes the direct-acting benzene ring present in norepinephrine pro-
(1R,2S) isomer of a-methylnorepinephrine se- vides excellent receptor activity for both a-
lective for a,-adrenoceptors over a,-adrenocep- and p-sites, but such catechol-containing com-
tors, affording the central antihypertensive pounds have poor oral bioavailability and
properties of methyldopa. short durations of action, even when adminis-
tered intravenously, because they are rapidly
5.1.3 R3 Substitution on Carbon-1. In the metabolized by COMT. Alternative substitu-
phenylethyamine series, a hydroxyl group at tions have been found that retain good activity
this position in the R absolute configuration is but are more resistant to COMT metabolism.
preferred for maximum direct agonist activity For example, 3'3'-dihydroxy compounds are
on both a- and p-adrenoceptors. If a hydroxyl not good substrates for COMT and, in addi-
is present in the S absolute configuration, the tion, provide selectivity for p,-receptors.
activity is generally the same as that of the Thus, because of its ring-substitution pattern,
corresponding chemical with no substituent. metaproterenol (18) is an orally active bron-
This is the basis for the well-known Easson- chodilator having little of the cardiac stimula-
Stedman hypothesis of three-point attachment tory properties possessed by isoproterenol
of phenylethanolamines to adrencoceptors (17).
through stereospecific bonding interactions Other substitutions are possible that en-
with the basic amine, hydroxyl group, and ar- hance oral activity and provide selective p,-
omatic substituents (85). A comprehesive and activity, such as the 3'-hydroxymethyl, 4'-hy-
excellent review of the stereochemistry of ad- droxy substitution pattern of albuterol (131,
renergic drug-receptor interactions was writ- which is also not a substrate for COMT. A re-
ten by Ruff010 (86). cently developed selective p,-agonist with an
An example of a phenethylamine agonist extended duration of action is salmeterol(21),
lacking an OH group on C-1 is dobutamine which has the same phenyl ring substitution
(27), which has activity on both a- and p-re- R4 as that of (13)but an unusually long and
ceptors but, because of some unusual proper- lipophilic group R1 on the nitrogen. The octa-
ties of the c h i d center on R1, the bulky nitro- noltwater partition coefficient log P for salme-
gen substituent, the overall pharmacologic terol is 3.88 vs. 0.66 for albuterol and the du-
response is that of a selective PI-agonist (87). ration of action of salmeterol is 12 vs. 4 h for
he (-)-isomerof dobutamine is an a,-agonist albuterol (88).
. . There is substantial evidence
and vasopressor. The (+)-isomer is a n a,- that the extended duration of action is attrib-
antagonist; thus, when the racemate is used uted to a specific binding interaction of the
clinically, the a-effects of the enantiomers ef- extended lipophilic side chain with a specific
fectively cancel, leaving the p-effects to pre- region of the P,-receptor, affording salmeterol
dominate. The stereochemistry of the methyl a unique binding mechanism (89). The long
Adrenergics and Adrenergic-Blocking Agents

lipophilic nitrogen substituent of salmeterol of enantiomers (1R,2R) and (1S,2S) consti-

has been shown, through a series of site-di- tute pseudoephedrine (?-ephedrine). Analo-
rected mutagenesis experiments, to bind to a gous to the catechol a-methylnorepinephrine
specific 10 amino acid region of transmem- (65, the active metabolite of methyldopa), the
brane domain 4 of the p,-adrenoceptor. This ephedrine stereoisomer with the (1R,2S) ab-
region, amino acids 149-158, is located at the solute configuration has direct activity on the
interface of the cyctoplasm and TMD4. Thus receptors, both a and P, as well as an indirect
"anchored" by the side chain, the remaining component. The ephedrine (IS,%) enantio-
part of the molecule can pivot and repetitively mer has primarily indirect activity. Pseudo-
ephedrine, the threo diastereomer of ephed-
stimulate the receptor through binding to as-
rine, has virtually no direct activity in either of
partate 113 of TMD3 and serines 204/207 of
its enantiomers and far fewer CNS side effects
TMD5. This lipophilic anchoring is postulated than those of ephedrine.
to keep the drug localized at the site of action
and produce the long duration of action of
At least one of the phenyl substituents
must be capable of forming hydrogen bonds
and, if there is only one, it should be at the
4'-position to retain P-activity. For example,
ritodrine (20) has only a 4'- OH for R4, yet (1R:2S) (1S:2R)
retains good p-activity with the large substitu- Ephedrine
ent on the nitrogen, making it P, selective.
If R4 is only a 3'- OH, however, activity is
reduced at a-sites and almost eliminated at
p-sites, thus affording selective a-agonists
such as phenylephrine (11)and metaraminol
(8). Further indication that a-sites have a
wider range of substituent tolerance for ago- (1R:2R) (1S:2S)
nist activity is shown by the 2',5'-dimethoxy
substitution of methoxamine (91, which is a
selective a-agonist that also has p-blocking ac-
Other phenylethylamines, such as amphet-
tivity at high concentrations.
amine and methamphetamine, which lack
When the phenyl ring has no substituents
both ring substituents and a side chain hy-
(i.e., R4 = H), phenylethylarnines may have droxyl, are sufficiently lipophilic to readily
both direct and indirect activity. Direct activ- cross the blood-brain barrier and cause dra-
ity is the stimulation of a receptor by the drug matic CNS stimulation, principally through
itself, whereas indirect activity is the result of indirect activity. The clinical utility of am-
displacement of norepinephrine from its stor- phetamine and its derivatives is entirely based
age granules, resulting in stimulation of the on CNS stimulant and central appetite sup-
receptor by the displaced norepinephrine. Be- pressant effects.
cause norepinephrine stimulates both a- and Thus, tamsulosin has no utility in treating
p-sites, indirect activity itself cannot be selec- hypertension, but far fewer cardiovascular
tive; however, stereochemistry of R1, R2, side effects than those of terazosin and dox-
andlor R4 may also play a role. azosin in treating BPH.
For example, ephedrine erythro-(5) and
pseudoephedrine threo-(5) have the same sub- 5.1.5 lmidazolines and Cuanidines. Although
stitution pattern and two asymmetric centers, nearly all P-agonists are phenylethanolamine
so there are four possible stereoisomers. The derivatives, a-adrenoceptors accommodate a
drug ephedrine is a mixture of the erythro en- far more diverse assortment of structures
antiomers (1R,2S) and (IS,%); the threo pair (80). Naphazoline (291, oxymetazoline (301,
5 Structure-Activity Relationships

tetrahydrozoline (311, and xylometazoline

(32)are selective a,-agonists and thus are va-
soconstrictors. They all contain a one-carbon
bridge between C-2 of the imidazoline ring and
a phenyl substituent; thus, the general skeleton
of a phenylethylarnine is contained within the
structures. Lipophilic substitution on the phe-
nyl ring ortho to the methylene bridge appears
to be required for agonist activity at both types
of a-receptor. Bulky lipophilic groups attached
The other imidazolines, (33)and (34), were
to the phenyl ring at the meta or para positions synthesized as analogs of (35) and were dis-
provide selectivity for the a,-receptor by dimin- covered to have properties similar to those of
ishing amnity for a,-receptors. a,-agonists. After the discovery of clonidine,
Closely related to the imidazoline a,-ago- extensive research into the SAR of central a,-
nists are the aminoimidazolines, clonidine agonists showed that the imidazoline ring was
(SS),apraclonidine (33), brimonidine (34); and not necessary for activity in this class. For ex-
the structurally similar guanidines, guana- ample, two ring-opened analogs of (35)result-
benz (36) and guanfacine (37). Clonidine was ing from this effort are guanabenz (10) and
originally synthesized as a vasoconstricting guanfacine (37). These are ring-opened ana-
nasal decongestant but in early clinical trials logs of clonidine, and their mechanism of ac-
was found to have dramatic hypotensive ef- tion is the same as that of clonidine.
fects, in contrast to all expectations for a vaso- Tolazoline (41) has clear structural simi-
constrictor (90). Subsequent pharmacologic larities to the imidazoline a-agonists, such as
investigations showed not only that clonidine naphazoline and xylometazoline, but does not
does have some a,-agonist (vasoconstrictive) have the lipophilic substituents required for
properties in the periphery but also that agonist activity. Phentolamine (40) is also an
clonidine is a powerful agonist at a,-receptors imidazoline a-antagonist but the nature of its
in the CNS. Stimulation of central postsyri8p- binding to a-adrenoceptors is not clearly un-
tic a,-receptors leads to a reduction in sympa- derstood.
thetic neuronal output and a hypotensive
5.1.6 Quinazolines. Prazosin (43),the first
effect. A very recent review thoroughly dis-
known selective a,-blocker, was discovered in
cusses the antihypertensive mechanism of ac-
the late 1960s (92) and is now one of a small
tion of imidazoline a,-agonists and their rela-
group of selective a,-antagonists, which in-
tionship to a separate class of imidazoline cludes two other quinazoline antihyperten-
receptors (91). sives, terazosin (44) (25, 93) and doxazosin
Similar to the imidazoline a,-agonists, (42). The latter, along with tamsulosin (241,
clonidine has lipophilic ortho substituents on was discovered to block a,-receptors in the
the phenyl ring. Chlorines afford better activ- prostate gland and alleviate the symptoms of
ity than methyls at a, sites. The most readily benign prostatic hyperplasia (BPH).
apparent difference between clonidine and the The first three agents contain a Camino-
a,-agonists is the replacement of the CH, on 6,7-dimethoxyquinazoline ring system at-
C-1of the imidazoline by an amine NH. This tached to a piperazine nitrogen. The only
makes the imidazoline ring part of a guanidino structural differences are in the groups at-
group, and the uncharged form of clonidine tached to the other nitrogen of the piperazine,
exists as a pair of tautomers. Clonidine has a and the differences in these groups afford dra-
pK, value of 8.05 and at physiologic pH is matic differences in some of the pharmacoki-
about 82% ionized. The positive charge is netic properties of these agents. For example,
shared over all three nitrogens, and the two when the furan ring of prazosin is reduced to
rings are forced out of coplanarity by the bulk form the tetrahydrofuran ring of terazosin,
of the two ortho chlorines as shown. the compound becomes significantly more wa-
Adrenergics and Adrenergic-Blocking Agents

ter soluble (94), as would be expected, given Labetalol(26) and carvedilol(59) have un-
tetrahydrofuran's greater water solubility usual activity, in that they are antihyperten-
than that of furan. sives with a,-, PI-, and Pz-blockingactivity. In
terms of SAR, you will recall from the earlier
5.1.7 Aryloxypropanolamines. In general, discussion of phenylethanolamine agonists
the aryloxypropanolamines are more potent that, although groups such as isopropyl and
P-blockers than the corresponding aryletha- t-butyl eliminated a-receptor activity, still
nolamines, and most of the p-blockerscurrently larger groups could bring back a,-affinity but
used clinically are aryloxypropanolamines. not intrinsic activity. Thus these two drugs
Beta-blockers have found wide use in treating have structural features permitting binding to
hypertension and certain types of glaucoma. both the a,- and both P-receptors. The
At approximately this same time, a new se- P-blocking activity of labetalol is approxi-
ries of Csubstituted phenyloxypropanolo- mately 1.5 times that of its a-blocking activity.
lamines emerged, such as practolol, which The more recently developed carvedilol has an
selectively inhibited sympathetic cardiac stim- estimated P-blocking activity 10 to 100 times
ulation. These observations led to the recogni- its a-blocking activity.
tion that not all preceptors were the same, A physicochemical parameter that has clin-
which led to the introduction of P, and P, no- ical correlation is relative lipophilicity of dif-
menclature to differentiate cardiac P-recep- ferent agents. Propranolol is by far the most
tors from others. lipophilic of the available P-blockers and en-
6 Recent Developments

ters the CNS far better than less lipophilic on efforts to discover new selective a,,-antag-
agents, such as atenolol or nadolol. Lipophilic- onists for treatment of prostatic hypertrophy
ity as measured by octanollwater partitioning and to develop selective P,-agonists for use in
also correlates with primary site of clearance. treating obesity and type 2 diabetes.
The more lipophilic drugs are primarily
cleared by the liver, whereas the more hydro- 6.1 Selective a!,,-Adrenoceptor Antagonists
philic agents are cleared by the kidney. This
The successful application of tamsulosin (24)
could have an influence on choice of agents in
to the treatment of BPH with minimal cardio-
cases of renal failure or liver disease (27).
vascular effects has led to an extensive effort
to develop additional antagonists selective for
6 RECENT DEVELOPMENTS the a,,-receptor. Phenoxyethylamine (102,
KMD-3213), a tamsulosin analog, has been re-
Recently, major research efforts in develop- ported to be in clinical trial in Japan, as has
ment of adrenergic drugs have focused largely (103) (95).
Adrenergics and Adrenergic-Blocking Agents

very thorough reviews of this field have re-

cently been published (96,97).

6.2 Selective P,-Agonists

The other major area of recent emphasis in
adrenergic drug research has been develop-
ment of selective &-agonists to induce lipoly-
sis in white adipose tissue. This area has been
extensively reviewed (4, 7, 8, 55, 98). Because
obesity and diabetes are reaching epidemic
proportions in the United States, an effective
weight reduction has enormous therapeutic
and market potential (99). As a consequence,
there is a veritable avalanche of potential new
drugs being published. To date several com-
pounds that looked promising in receptor as-
says and animal studies have entered clinical
trials and failed. The reader should consult
the listed reviews for extensive descriptions of
Other series of highly selective a,,-antag- the progress in this field through 2000. Some
onists, and representative examples, are of the most promising recent candidates have
arylpiperazines, arylpiperidines, and piperi- been an extensive series of 3'-methvlsulfon-

dines, represented by (104), (1051, and (1061, amido-4'-hydroxyphenylethanolamines pre-

respectively. Several compounds in these se- pared by competing groups. Compounds (107)
ries have entered clinical trials, but little has (BMS-194449) and (108) (BMS-196085) have
been reported about the outcomes (95). In ad- both gone into clinical trial but are reported to
dition to the review by Bock (951, two other have failed (100,101).

In a second series, compounds (109-111) 2. J. Oostendorp, et al., Br. J. Pharmacol., 130,

were reported as the most active derivatives in 747-758 (2000).
the compounds reported in each study (102- 3. T. Horinouchi, Y . Yamarnoto, and K. Koike,
104). Finally, compounds (112) and (113) Pharmacology, 62,98-102 (2001).
from the same publication were reported to be 4. T . H . Claus and J. D. Bloom, Ann. Rep. Med.
among the most potent and selective human Chern., 30,189-196 (1995).
P3-agonistsknown to date (105). 5. A. D. Strosberg and F. Pietri-Rouxel, Trends
Another group reported another series of Pharmacol. Sci., 17, 373-381 (1996).
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selective a,,-antagonists and selective P3-ago- Des., 7, 1433-1449 (2001).
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The University of Iowa
Iowa City, Iowa

1 Introduction, 40
2 Cholinergic (Acetylcholine) Receptors, 41
3 Acetylcholine and Analogs, 43
3.1 Variations of the Quaternary
Ammonium Group, 43
3.2 Variations of the Acyl Group, 45
3.3 Variations of the Ethylene Bridge, 46
3.4 Substitution of the Ester Group
by Other Groups, 47
4 Cholinergics Not Closely Related Structurally to
Acetylcholine, 49
4.1 Nicotine, Its Analogs and Congeners, and
Other Nicotinic Receptor Stimulants, 49
4.2 Muscarine, Muscarone, and Related
Compounds, 57
4.3 Pilocarpine and Analogs and Congeners, 61 .
4.4 Arecoline and Analogs and Congeners, 62
4.5 Oxotremorine and Analogs and Congeners,
4.6 Miscellaneous, Structurally Unique
Muscarinic Agonists, 78
5 Conformation-Activity Relationships of Some
Cholinergic Agonists, 80
6 Anticholinesterases, 84
6.1 Quaternary Ammonium Reversible
Inhibitors, 85
6.2 Reversible, Noncovalent Inhibitors Related
to 1,2,3,4-Tetrahydro-
9-Aminoacridine, 86
6.3 Carbamate-Derived Inhibitors, 88
6.4 Phosphorus-Derived Inhibitors, 90
6.5 Miscellaneous Inhibitors, 93
7 Acetylcholine-Release Modulators, 97

Burger's Medicinal Chemistry and Drug Discovery

Sixth Edition, Volume 6: Nervous System Agents
Edited by Donald J. Abraham
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc.

1 INTRODUCTION Therapeutic indications for cholinergics,

anticholinesterases, and/or acetylcholine re-
The transmission of impulses throughout the leasing agents in contemporary practice or
cholinergic nervous system is mediated by ace- those contemplated for future use include the
tylcholine (I), and compounds that produce following:

1. Relief of postoperative atony of the gut and

the urinary bladder. In such conditions,
cholinergic stimulation may relieve the sta-
sis by stimulating peristaltic movements of
their pharmacologic effects by mimicking or the intestine and ureters and by constric-
substituting for acetylcholine are called cho- tion of the bladder.
linergics or parasympathomimetics. 2. Reduction of intraocular pressure in some
Compounds that inhibit or inactivate the
types of glaucoma, by increasing the drain-
body's normal hydrolysis of acetylcholine by
acetylcholinesterase in nervous tissue and/or age of intraocular fluid through the canal of
by butyrylcholinesterase (pseudocholinester- Schlemm.
ase, cholinesterase) in the plasma are called 3. Relief of muscular weakness in myasthenia
anticholinesterases. The gross observable gravis. This condition reflects a failure of
pharmacological effects of both types of com- an appropriate amount of acetylcholine to
pounds are quite similar. More recently, com- reach cholinergic receptors on the post-
pounds have been found that enhance the re- myoneural junctional membrane following
lease of acetylcholine from cholinergic nerve rapidly repetitive nerve impulses. The re-
terminals, thus (like the anticholinesterases) duced level of acetylcholine may result
producing cholinergic effects by an indirect from excessive enzyme-catalyzed hydroly-
mechanism. sis of it or from diminished production or
Choline is taken into the nerve terminal release; the etiology of the disease usually
from the synaptic cleft by a sodium-depen- involves an autoimmune response phe-
dent, high-affinity active transport process, nomenon, primarily to the acetylcholine re-
which is the rate-limiting step in the biosyn- ceptor at the postjunctional end plate (5).
thesis of acetylcholine in the nerve terminal However, in approximately 10%of patients
(1). In the nerve terminal, choline reacts with demonstrating the myasthenic syndrome,
acetylcoenzyme A in a process catalyzed by the cause is congenital and in these individ-
choline acetyltransferase. The acetylcholine uals, traditional cholinergic therapy is inef-
thus synthesized is sequestered in the synap- fective (5).
tic storage vesicles in the nerve terminal for 4. Relief of the symptoms of Alzheimer's dis-
future use as a neurotransmitter. The active ease and some other types of senile demen-
transport of acetylcholine into the storage ves- tia. A deficiency of functional cholinergic
icles has been reviewed (2). Vesamicol (2) at neurons, particularly those extending from
micromolar concentrations blocks transport the lateral basalis, has been observed in pa-
of acetylcholine into the vesicles (3,4). tients with progressive dementia of the
Alzheimer type (6). Cholinomimetic ther-
apy has been directed at compensating for
the inadequate cholinergic activity in these
neurons. However, clinical results with
- and anticholinesterases have
often been disappointing or inconsistent
due, in some instances, to the inability of
quaternary ammonium drugs to penetrate
2 Cholinergic (Acetylcholine) Receptors

the blood-brain barrier or to a lack of spec-

ificity or selectivity of the drug for the cho-
linergic receptorb) involved in the patho-
logical condition. There continues to be
great emphasis on the search for and study
of nonquaternary ammonium molecules
(having greater lipophilic character) that
will penetrate the blood-brain barrier and
interact with appropriate acetylcholine re-
ceptors in the brain. Thus older tertiary
amine drugs such as pilocarpine and areco-
line, which demonstrate only modest cho-
linergic activity and are classed as partial
agonists, have been the subjects of intense
structure-activity studies. Relief of Alzhei-
mer symptoms by reinforcement of central
cholinergic activity by inhibition of acetyl-
cholinesterase has been the subject of a tre- is a true cholinergic agonist, it is recognized
mendous research effort (see Section 6). that nicotine lacks agonist effect in some parts
The utility of cholinergics in correction of of the nervous system; some of its peripheral
other types of deficits in memory and learn- actions are indirect and probably involve pre-
ing has been investigated for many years synaptic release of acetylcholine (10-14).
(7),with largely inconclusive results. How- Muscarinic receptors occur peripherally at
ever, this remains a fascinating and a po- parasympathetic postsynaptic sites on glands
tentially significant area of research. and smooth (nonstriated) muscles, and they
5. Relief from pain. Selected cholinergic are involved in gastrointestinal and ureteral
agents have been found that display an- peristalsis, pupillary constriction, peripheral
tinociceptive (analgesic) effects grossly vasodilatation, reduction of heart rate, and
similar to those of morphine. Most of these promotion of exocrine glandular secretion
are nicotinic receptor agonists, but a mod- (salivary glands, sweat glands, tear glands).
est number of muscarinic agonists have Autonomic ganglia also contain muscarinic re-
been found that also display antinocicep- ceptors. Peripheral nicotinic receptors are
tive effects. found postsynaptically on striated (voluntary)
6. Relief of symptoms of Parkinson's disease. muscle fiber membranes and in all autonomic
Acetylcholine receptors of the nicotinic ganglia (sympathetic as well as parasympa-
type have been implicated in the Parkinso- thetic). There are also nicotinic and musca-
nian syndrome (7-9). rinic pathways in the central nervous system.
Muscarinic receptors are subcategorized as
M,, M,, M,, M,, and M, (15). By definition, M,
2 CHOLlNERGlC (ACETYLCHOLINE) receptors occur especially in the cerebral cor-
RECEPTORS tex and hippocampus, where they are thought
to play an important role in learning and
Acetylcholine receptors have been subdivided memory processes (16). It has been assumed
into two major pharmacological types (musca- for some years that M, receptor agonists are
rinic and nicotinic), based on their selective the most likely candidates for treatment of
response to two alkaloids: muscarine (3) and cholinergic deficits involved in Alzheimer's
nicotine (4). disease (17). MI receptors are found peripher-
Neither nicotine nor muscarine is a normal ally in autonomic ganglia where they are in-
physiological component of the mammalian volved in membrane depolarization, which is
body; hence the muscarinic/nicotinic classifi- mediated by stimulation of phospholipase C
cation of acetylcholine receptors is artificial. and subsequent production of inositol-1,4,5-
Although it is well established that muscarine triphosphate and diacyl glycerol (18). M, re-

ceptors are present in the cerebellum, heart, have a similar pentameric structure, but they
smooth muscle, and at some potassium chan- vary considerably in the nature of the subunit
nels (15); M, receptors are found in secretory combinations (29).
. .

glands and smooth muscle. M, receptors are At least some neuronal nicotinic subunits
located in the basal forebrain and the stria- are homologous to those found in muscle.
tum. M, receptors are found in the substantia These have been designated as a if they con-
nigra. MI, M,, and M, receptors modulate tain vicinal cysteine residues analogous to
some potassium, chloride, and calcium chan- Cys192-Cys193of the Torpedo receptor, or P if
nels, and M, and M, receptors modulate some they do not. Stimulation of these receptors
calcium channels (19). All of these ion channel produces depolarization (a result of cation
effects are indirect and complex. The central channel opening) and firing of the postgangli-
nervous system contains all known subtypes onic neuron. Nine homologous nicotinic recep-
of muscarinic receptors (18).Both muscarinic tor subunits have been identified thus far in
M, (20) and nicotinic (21) receptors decrease mammalian nervous systems (30). Two main
in numbers with the progression of Alzhei- categories of nicotinic receptor pentamers
mer's syndrome, whereas the numbers of have been identified in the brain, based on
M, receptors do not decrease (22). Alzheimer their high affinity for either nicotine or for the
patients also show reduced activity of acetyl- nicotinic receptor blocker a-bungarotoxin.
cholinesterase; of high affinity, sodium-depen- The former are considered to be formed by a4-
dent choline uptake; and of choline acetyl- and P2-subunit receptors, and the latter are
transferase (23). Contemporary and projected thought to be a7 or a7* nicotinic receptors
therapeutic roles for muscarinic receptors in (30). Nicotinic receptor glycoprotein has been
the central nervous system have been re- isolated and extensively " studied (31-33). Re-
viewed (24). views of the classification, recommended no-
Muscarinic receptors are glycoproteins menclature, and function of nicotinic receptor
with molecular weights of approximately subtypes are available (29,30,34-36).
80,000. They are located on the outer surface A family of presynaptic ion channel-type
of the cell membrane, and they are of the G- acetylcholine receptors in the brain modulates
protein-linked type; M,, M,, and M, receptors the release of acetylcholine, dopamine, and
couple with G, proteins to stimulate phospho- other neurotransmitters implicated in learn-
lipase-C, whereas M, and M, receptors couple ing and memory processes (37). There is con-
with Gi proteins to inhibit adenylate cyclase vincing evidence to implicate a deficit in nico-
(25). The molecular basis of muscarinic recep- tinic receptors in the symptomatology of
tor function has been reviewed (26). Nordvall Alzheimer's disease. Furthermore, the neuro-
and Hacksell (27) proposed a molecular model toxin P-amyloid attenuates nicotine-induced
of the transmembrane domains of the M, re- release of acetylcholine and dopamine (37).
ceptor, to explain the three-dimensional inter- Although acetylcholine is optically inac-
action of the receptor with its ligands. How- tive, its in vivo receptors exhibit discrimina-
ever, the authors specified that the model is tion between enantiomers of synthetic and
"primarily of qualitative value". naturally occurring cholinergic stimulants.
Postsynaptic nicotinic receptors in the pe- Both central and peripheral muscarinic recep-
ripheral nervous system are designated as N, tors are highly stereospecific; peripheral nico-
(in autonomic ganglia) and N, (at myoneural tinic receptors seem to be less so, although
junctions). Nicotinic receptors are of the ion these usually show preference for one or the
channel type. They are pentameric proteins other member of enantiomeric pairs. Central
that are composed of one, two, or more distinct nicotinic receptors frequently demonstrate a
subunits, each of which contains multiple higher degree of stereoselective binding char-
membrane-spanning regions, and the individ- acter than is noted with the peripheral recep-
ual subunits surround an internal channel tors. Understanding of nicotinic receptor ste-
(28). Nicotinic receptors are highly heteroge- reoselectivity and specificity is complicated by
neous, and subcategorization has been diffi- the liklihood that, as was mentioned previ-
cult; those in neuronal tissue are believed to ously, at some in vivo sites, some nicotinic
3 Acetylcholine and Analogs

stimulant agents function indirectly by pro- these older studies were performed before the
moting presynaptic release of acetylcholine. exquisite heterogeneity of both muscarinic
and nicotinic receptors was recognized; thus,
3 ACETYLCHOLINE AND ANALOGS many compounds were classified merely as
"muscarinic" or "nicotinic." The observed ef-
Acetylcholine has virtually no clinical uses. Its fectiveness of a cholinergic agent in producing
rapid rate of hydrolysis in the gastrointestinal a biological response depends, inter alia, on its
tract precludes oral administration, and a sim- inherent potency and intrinsic activity as well
ilarly rapid hydrolysis by esterases in the as on the rate at which it is metabolically in-
blood and by acetylcholinesterase in the ner- activated and/or excreted. Frequently, these
vous tissue limits its usefulness. individual factors were not separately and in-
The need for therapeutically satisfactory dividually assessed. This problem has been
cholinergic agents coupled with the simple cited (40) with regard to the lack of consis-
and easily synthesized structures necessary tency among laboratories in the methods used
for cholinergic activity have stimulated prep- to determine cholinergic receptor subtype se-
aration and study of a great number of analogs lectivity. Therefore, in the following discus-
of acetylcholine. The following structural vari- sion of the relationship of chemical structure
ations have been addressed: to cholinergic activity, frequently only gener-
alized (and tentative) conclusions can be
1. Alteration of the quaternary ammonium made, and these may have been based on a
head. composite of the cholinergic activities for
2. Replacement of the acetyl group by other which the compound was tested.
acyl moieties.
3.1 Variations of the Quaternary
3. Alteration of the ethylene bridge connect- Ammonium Croup
ing the quaternary ammonium and the es-
ter groups. Two types of alterations of the quaternary
4. Substitution of another group for, or elim- head have been studied: replacement of the
ination of, the ester moiety. nitrogen by other atoms and replacement of
the N-methyl groups by hydrogen, alkyl, ni-
trogen, or oxygen. Acetyl phosphonocholine
The "five atom rule," first suggested by
( 5 ) (391, acetylarsenocholine (6) (391, and ace-
Alles and Knoefel (38) and stated more for-
mally by Ing (39), proposes that, for maximum
muscarinic activity, there should be attached
to the quaternary nitrogen atom, in addition
to three methyl groups, a fourth group with a
chain of five atoms, as illustrated for acetyl-
choline: C-C-0-C-C-N. This empirical obser-
vation has been found to be valid for a large
number of molecules, regardless of the precise tylsulfonocholine (7) (41) exhibit muscarinic
nature of the five atoms involved. effects, but they are considerably less potent
Studies of a large number of compounds than acetylcholine.
have supplied considerable information on Ing (39) noted that the potencies of acetyl-
structural requirements for cholinergic activ- choline analogs containing charged atoms
ity; however (especiallyin the older literature) other than nitrogen (phosphorus, arsenic, sul-
these data must be interpreted with caution. fur) are in inverse order to the volumes occu-
They have been obtained using a variety of in pied by these atoms. The carbon isostere (8) of
vivo and in vitro testing procedures and bio- acetylcholine exhibits no cholinergic activity,
logical preparations in a variety of animal spe- but it is an excellent substrate for acetylcho-
cies, and different biological responses associ- linesterase (42). Studies of the role of nitrogen
ated with stimulation of the cholinergic substituents in the acetylcholine molecule in-
nervous system were measured. Additionally, dicate that the N,N,N-trimethyl quaternary

Table 2.1 Representative Esters of Choline

Number R Reference
N-methyl,N,N-diethylcholine,and it is decid-
H,NCH2C0 edly more potent than the diethylcholine es-
n-C3H7C0 ter.
i-C3H7C0 However, in general, incorporation of the
n-C4H,C0 choline nitrogen into a heterocyclic ring mark-
C6H5C0 edly lowers the potency compared with acetyl-
C6H5CH2C0 choline (47,48).
C6H5CH=CHC0 The report (49) that the tertiary amine (12)
(C$,)&XOH)CO is a full and nonselective muscarinic agonist

lends credence to proposed significance of mo-

lecular rigidity in muscarinic agonism.
ammonium pattern of acetylcholine itself Replacement of one N-methyl group of ace-
is optimum for potency and activity. The ace- tylcholine by ethyl permits retention of most
tate esters of N,N-dimethylethanolamine,N- of the cholinergic activity, but as more
methylethanolamine, and ethanolamine pos- N-methyl groups are replaced by ethyl, there
sess weak muscarinic activity, and they show is a progressive loss of cholinergic effect (50).
no nicotinic activity (43). The tertiary m i n e When one N-methyl is replaced by n-propyl or
congener of carbamyl choline (Table 2.1, 19) n-butyl, there is almost complete loss of cho-
exhibits greatly diminished nicotinic and mus- linergic activity (41).
carinic effects compared with the N,N,N-tri- The hydrazinium congener (9), in which
methyl quaternary compound (44).These con- one N-methyl is replaced by NH,, was less ac-
clusions seem valid for cholinergic agents tive than acetylcholine in all assays performed
having, like acetylcholine,a high degree of mo- (51). The tris-(trideuteromethyl) congener
lecular flexibility. In contrast, in certain ace- (10) showed similar potency to acetylcholine
tylcholine congeners in which the nitrogen is a in a dog blood pressure assay (52).
part of a relatively rigid ring system (pyrroli- Replacement of one N-methyl in acetylcho-
dine, morpholine, piperidine, quinuclidine), line and in three congeners (13-16) by me-
tertiary amine salts are more potent musca-
rinics than their quaternary derivatives (45).
This enhanced activity of the tertiary amines
has been rationalized on conformational
grounds. It is assumed that the tertiary
amines are protonated at their in vivo sites of
The pyrrolidine compound (11)is 20-33%
as potent as acetylcholine (46); this compound
can be viewed as a cyclic congener of acetyl
3 Acetylcholine and Analogs

thoxyl permits retention of some cholinergic 3.2 Variations of the Acyl Croup
effects, and in certain compounds, nicotinic or
Qualitatively, choline has the same pharmaco-
muscarinic activities are enhanced over the
parent N,N,N-trimethyl system (53). logical actions as acetylcholine, but it is far
The reverse N-alkoxy systems (17) demon- less active at most sites (58). However, choline
strated only extremely weak muscarinic activ- has been reported (34) to be a full agonist at
one nicotinic receptor subtype, and at some
other nicotinic subtypes it can act as a partial
agonist or a coagonist.
Acetylation of the alcohol function of cho-
line greatly increases the potency. However,
(17) R = CH3 or NH2 formylcholine is less potent than acetylcho-
line, and homologation of the acetate methyl

R', R = combinations of H, CH3
group of acetylcholine generally produces
compounds that are much less potent than
ity (54). These compounds violate the five acetylcholine (see Table 2.1). Polar groups
atom rule. such as OH (Table 2.1,17) and NH, (4) mark-
Amine oxide analogs of the cholinergic ago- edly decrease muscarinic potency, but a
nists (18-21) exhibit little or no cholinergic group (16) permits retention of considerable
effect, and they are not substrates for cho- activity. Bromoacetylcholine (number 2) is a
linesterases (55). muscarinic and nicotinic agonist (59) and, un-
der reducing conditions, it binds covalently to
nicotinic receptors but not to muscarinic re-
ceptors (60).
Acrylylcholine (Table 2.1, 151, which has
been isolated from tissues of a marine gastro-
pod (72), has relatively high cholinergic activ-
ity. Higher fatty acid esters (12 and 13) were
prepared for testing as hemolytic agents, but
apparently they have never been evaluated for
cholinergic activity. A study of acetylcholine
congeners derived from relatively high molec-
ular weight acids (73), most of which con-
The observed biological effects of several tained a benzene ring, revealed that as the
variations of the quaternary head of acetyl- molecular weight of the acid increases para-
choline and its congeners may be rationalized sympathetic stimulant activity dimninishes,
by invoking results of molecular orbital calcu- and there is a gradual change to atropine-like
lations (56), which indicate that in both mus- (muscarinic blocking) activity.
carine and acetylcholine the nitrogen atom is In general, carbamic acid esters of choline
nearly neutral and a large part (70%) of the and its congeners are more potent and more
formal charge is distributed among the three toxic than the corresponding acetates. Car-
attached methyl groups, which form a large bamyl choline (19 in Table 2.1) is a potent
ball of spreading positive charge. muscarinic agent, and it demonstrates pro-
Furthermore, Kimura and coworkers (57) nounced nicotinic stimulant effects a t auto-
determined that chain extension of one alkyl nomic ganglia. It is likely that these ganglionic
group of the tetramethylammonium cation actions are due, at least in part, to release of
produces a great decrease in the charge den- endogenous acetylcholine from the terminals
sity on the nitrogen, and they proposed that of cholinergic fibers (74).
cholinergic agonist activity for a quaternary Carbamyl choline is is a poor substrate for
ammonium compound requires a minimum acetylcholinesterase and nonspecific cholines-
level of charge density on the nitrogen. terases (74). The nitrate ester (18, Table 2.1)

has marked nicotinic and muscarinic agonist 3.3 Variations of the Ethylene Bridge
effects, and it also displays an intense paralyz- The distance between the ester moiety and the
ing nicotine action. The dimethylphosphate
cationic head of acetylcholine seems to be crit-
ester (20,Table 2.1) has powerful nicotinic ac- ical. Acetoxytrimethylammonium (27), com-
tion but little muscarinic effect.
The "reversed ester" congener (22)of ace-
tylcholine exhibits weak muscarinic and no

pletely lacking the ethylene bridge of acetyl-

choline, showed a pharmacological profile
quite similar to acetylcholine (79), but it was
nicotinic effects (75). In contrast, the carbon- much less potent.
ate congener (23) is a full agonist at musca- Acetoxymethyltrimethylammonium (28)
rinic and nicotinic receptors, with an activity appeared to have little or no muscarinic effect

on a guinea pig ileum preparation (76). The

approximately one order of magnitude less profound instability of this compound in solu-
than that of acetylcholine (76). tion precluded collection of quantitative data.
Acetylthiocholine (24) and acetylseleno- An older report (68) had indicated that struc-
choline (25) exert acetylcholine-like effects on ture (28) has "intense muscarinic action" and
the guinea pig ileum and on the frog rectus "marked nicotine stimulant action." Acetyl
abdominis, but they are somewhat less potent y-homocholine (29) is decidedly less potent1
than acetylcholine (77). active than acetylcholine (73). CAcetoxybu-
Unesterified thiocholine and selenocholine tyltrimethylammonium (30) exhibits ex-
display a relatively high degree of acetylcho- tremely weak muscarinic and nicotinic effects
line-like potency and activity compared with
their acetate esters, in contrast to the dra-
matic potency difference between choline and
acetylcholine. The biological effects of these
unesterified thiols and selenols have been sug-
gested to be due to their oxidation to disulfide
and diselenide derivatives (77). The amide
congener (26) of acetylcholine has little or no
Replacement of one or more of the hydro-
gen atoms of the ethylene bridge with alkyl
groups produces marked changes in potency
and activity. Acetyl p-methylcholine (31) is
equipotent to acetylcholine as a muscarinic
agonist, but it has a much weaker nicotinic
action (74). A factor in the observed potency of
acetyl p-methylcholine is its slower rate of hy-
cholinergic activity (68). Acetylthionocholine, drolysis by acetylcholinesterase because of
in which the carbonyl oxygen of acetylcholine poor affinity of the compound for the enzyme's
is replaced by sulfur, displayed some acetyl- catalytic site (81) and its extremely high resis-
choline-like effects in an electroplax prepara- tance to hydrolysis by nonspecific serum cho-
tion (78). linesterases.
3 Acetylcholine and Analogs

num sites (86) and of 915 using guinea pig

intestinal muscle (87); the S antipode is the
(33)exhibits 14% of the muscarinic potency of
acetylcholine, and it is almost completely re-
sistant to a~et~lcholinesterase; the (+)-threo
isomer is inert as a cholinergic and is a poor
Acetyl a-methylcholine (32) is a more po- substrate for acetylcholinesterase (88). These
tent nicotinic than a muscarinic, but both racemic mixtures have apparently never been
effects are decidedly less than those of acetyl- resolved.gem-Dimethyl substitution of acetyl-
choline (82); it is hydrolyzed by acetylcho- choline, either on the a,a or the p,p positions
linesterase at a rate similar to that of acetyl- of the choline moiety, greatly reduces but does
choline (73). The carbarnate ester of (*I+- not abolish muscarinic activity (89). Both
methylcholine (34), bethanechol, is a useful compounds are relatively poor substrates for
bovine erythrocyte acetylcholinesterase. Re-
placement of the C-methyl groups in the eth-
ylene bridge by longer chains causes an in-
crease in toxicity and a reduction in
muscarinic activity, e.g., the acetate esters of
p-n-propyl- and p-n-butylcholines (90, 91).

3.4 Substitution of the Ester Group

therapeutic agent, and acetyl p-methylcholine by Other Groups
(31) has some limited diagnostic uses (84).
The introduction of the C-methyl group into The ester moiety of acetylcholine does not ap-
the acetyl a- and P-methylcholine molecules pear to be essential for cholinergic activity. In
creates a chiral center, and the enantiomers general, alkyl ethers of choline and of thiocho-
exhibit different properties (Table 2.2). line are less potent and less active than acetyl-
S-(+)-Acetyl-p-methylcholine(the euto- choline (47); thio ethers are less potent than
mer) is hydrolyzed by acetylcholinesterase at the corresponding oxygen compounds. Con-
about half the rate of acetylcholine; the R-(-1- trary to some earlier literature reports, the
enantiomer is a weak inhibitor of the enzyme vinyl ether of choline (36) is not a more potent
(82). Work of Ringdahl (85) suggests that the muscarinic agent than the ethyl ether (35)
markedly lower pharmacological activity of (both are weak muscarinics), but it is a better
R-(-)-acetyl-p-methylcholineis a result both nicotinic agent, displaying higher potency
of lower affinity for the muscarinic receptor(s) than acetylcholine (92).
and lower intrinsic activity. The antipodes of a-Methyl substitution of choline in its ethyl
carbamyl-p-methylcholine (bethanechol) (34) and vinyl ethers (compounds 38 and 40)
displayed a eudismic ratio of 740 at rat jeju- greatly diminishes muscarinic potencies but

Table 2.2 Muscarinic Activities of Acetyl C-Methylcholinesa

Number Moles Equivalent to 1 Mole
of AcCh as Agonist in Guinea Pig Activity Ratio,
Substituent Stereochemistry Ileum (+)I(-)
a-CH3 RS 49
S-(-1- 232 8
R-(+)-(eutomer) 28
p-CH3 RS 1.58
S-(+)-(eutomer) 1.01 240
R-(-1- 240
"Adapted from Ref. 83. Courtesy of Plenum Press.

ethers (43) in which the choline moiety was a

part of the ring system.

permits retention of potent nicotinic effects. It was concluded that the nicotinic activity
p-Methyl substitution (compounds 37 and 39) of choline phenyl ether and of choline o-tolyl
permits retention of some degree of musca- ether is a reflection of the ability of the mole-
rinic effect, but nicotinic effects are com- cule to assume a "planar" conformation when
pletely abolished (92). A series of open-chain interacting with the ganglionic nicotinic re-
congeners of muscarine, typified by structure ceptor. In contrast, the inactive 2,6-xylylether
(41), exhibited low muscarinic potency, which of choline cannot assume this planar disposi-
tion. Evaluation of additional conformation-
ally restricted aryl choline ethers (44-47) re-
vealed that only the piperidine derivative (47)
is a ganglionic stimulant (98).

was ascribed by Friedman (47) to the com-

pounds' stereochemical heterogeneity.
An open chain analog (42) of desmethyl-
muscarine lacking chiral centers exhibited ex-
tremely low muscarinic activity (93).

Some aromatic ethers of choline display

marked nicotinic activity, but they are inac-
tive at muscarinic sites (94). The o-tolyl ether
of choline is a potent ganglionic stimulant Ketonic systems (48a-c), carbon isosteres
(95), but the 2,6-xylyl ether of choline is inert of the ester moiety, display weak activities,
as a nicotinic agent (96). and they are predominantly more nicotinic
Additional ring-substituted phenyl ethers than muscarinic (47).
of choline were described by Hey (94). Clark The secondary alcohol analogs of these ke-
and coworkers (97) studied conformationally tones are even weaker and the thio ketones
restricted racemic bicyclic choline phenyl are also weak (48).
4 Cholinergics Not Closely Related Structurally to Acetylcholine



4.1 Nicotine, Its Analogs and Congeners,

and Other Nicotinic Receptor Stimulants
Naturally occurring levorotatory nicotine (4)
has the S- absolute configuration. Its enantio-
mer, R-(+)-nicotine, was decidedly less potent
than the naturally occurring material in as-
says for peripheral effects (99). The pyrroli-
dine methyl quaternary derivative of S-(-1-
nicotine (50) shows peripheral activity com-

parable to that of nicotine itself (100) but it

lacks the secondary blocking action of the ter-
tiary arnine. In contrast, N-alkylation of the
(48a) R = CH3; alkylene = CH2-CH2 pyridine ring nitrogen of S-nicotine produces
(48b) R = CH3; alkylene = (CHz)3 quaternary compounds that are potent and se-
(48c) R = CzH5; alkylene = CH-CH2 lective antagonists at nicotinic receptor sub-
I types (101). The dimethiodide salt of S-nico-
tine has a low order of potency (100).
Nornicotine, in which the N-methyl is re-
In a series in which an alkyl chain (methyl placed by hydrogen, is somewhat less potent
through n-amyl) replaces the acetate ester and active than nicotine in most assays (102).
moiety (49), minimum activity occurs in most R- and S-nornicotine are equipotent with
assays when R = ethyl or n-propyl, and maxi- R-(+)-nicotine, the less active, unnatural en-
antiomer, in a rat brain membrane-binding
assay (103). In that study, S-(-)-nicotinewas
13 times more potent than its R- enantiomer.
Replacement of the N-methyl of nicotine with
ethyl or n-propyl causes an exponential loss of
peripheral nicotinic effect (102). Anabasine
mum muscarinic potency is demonstrated (51),a relatively minor alkaloidal constituent
when R = n-amy1(47,48), consistent with the of tobacco, demonstrated approximately 1/10
five-atom rule. the affinity of nicotine in a binding assay
Above heptyl, the compounds become an- (104). A synthetic azetidine congener (52) of
tagonists to acetylcholine. Numerous exam- nicotine binds with the same affinity as nico-
ples of ketones and N-alkyl congeners have tine to rat brain membrane tissue, and it dis-
been tabulated (47,481. played a greater potency than nicotine in a rat
An earlier review (47) descibes the pharma- behavioral assay (105). Evaluation of a series
cology of additional analogs and congeners of of 6-substituted nicotine derivatives (53) led
acetylcholine. to the conclusion that affinity for rat brain

(without cerebellum) nicotinic receptors is re-

lated to the lipophilicity of the 6-substituent,
as well as to the size of the substituent (106).
Electronic factors seem to play a less signifi-
cant role.

A nicotine structural isomer (57) retains a

considerable degree of nicotine-like activity
(102). The piperidine congener (58) is some-
what less potent and active, and the perhy-
droazepine congener (59) is inert. The pyr-
rolidine and piperidine ring N-methyl quater-
nary derivatives of compounds (57) and (58)
are slightly less active than the corresponding
tertiary bases (107). Glennon and coworkers
(108) reported that the 6,7,8,9-tetrahydro-5H-
pyrido[3,4-dlazepines (60a and 60b) showed
high aMinity for nicotinic receptors in rat
brain (without cerebellum). The pyrido[3,4-.
clazepines (61a and 61b) had much less aMin-
Synthetic compounds (54) representing ity for the receptors (cf. compound 59). These
structures in which each of the bonds of the workers (108) reported additional &substi-
pyrrolidine ring of nicotine is cleaved, one by tuted pyridine systems in which the substitu-
one, produced a series of "seconicotines" ent was w-aminoalkyl, aminopropenyl, amino-
(102). propynyl, and aminoethoxy. Some of these
derivatives bound to nicotinic receptors, but it
was not possible to arrive at structure-activity
conclusions from these data.

Only the open chain congeners (55) and

(56) display nicotine-like activity. The potency
of compound (55) is increased in its N,N-di-
methyl congener; in contrast, the N,N-di-
methyl derivative of compound (56) is inert.
4 Cholinergics Not Closely Related Structurally to Acetylcholine 51

When n = 2, all positions of attachment to

the pyridine ring (carbon 2, 3, or 4) result in
extremely low potency and activity. When n =
1, attachment to positions 2 and 4 produces
practically inert compounds (102). Replace-
ment of the pyridine ring of structure (57) by
bioisosteric benzene, 2-thienyl, 2-furanyl, and
2-pyrrolyl ring systems abolishes almost all
nicotine-like activity.
The findings that S-nicotine ameliorates
some of the symptoms of the Alzheimer syn-
drome (110) and has a neuroprotective effect
in animals (111)have stimulated increased in-
terest in nicotine analogs and congeners.
Members of a series of 3'-, 4'-, and 5'-substi-
tuted nicotine analogs (64) were evaluated as

ligands for a nicotinic receptor from rat brain

The R-enantiomer of the pyridylquinucli- membranes (112).
dine (62) has a slightly higher affinity for a$, Only a small substituent is tolerated at posi-
nicotinic sites than the S-enantiomer (109). tion 4'; the (2'-S,4'-R)-methyl congener is the
most potent of the entire series, but it is some-
what less potent than S-nicotine itself. None
of the 3'- or 5'-substituted analogs approach
this binding affinity. 2-Chloronicotine (65) is
exponentially less potent than nicotine in an
a,& nicotinic receptor binding assay, whereas
6-chloronicotine (66) is twofold more potent

The S-enantiomer is 20 times less potent at

ganglionic subtypes than is the R.
Further modifications of compound (57)
are illustrated in structure (63).

than nicotine (113). The stereochemistry of

these chloronicotines was not addressed.
From a study of insecticidal nicotinic
agents (114) imidacloprid (67) was reported to

act selectively at the insect versus the mam-

malian nicotinic acetylcholine receptor(s). In
contrast, the desnitro compound (68),a mam-

and active of the enantiomeric pair. Its effects

were blocked by the nicotinic antagonist
Antinociceptive (analgesic) activity of (S)-
(-)-nicotine has been observed and docu-
mented in many animal species (117). (- )-Epi-
malian minor metabolite of (67), is selective batidine (711, extracted from the skins of a
for the mammalian versus the insect nicotinic
receptor(s) and it is similar to (-)-nicotine in
potency in a mouse brain binding assay (115).
In a series of substituted 2-arylpyrrolidines
in which the substituted aryl group is a bio-
isosteric replacement for the pyridine ring of
nicotine, it was found that the isoxazole deriv-
ative (69) is a potent cholinergic channel acti-
vator (116).

South American frog, Epipedobates tricolor, is

200-400 times more potent than morphine as
an analgesic (118).
The stereochemistry of (-)-epibatidine
(lR,2R,4S)has been established by several to-
tal syntheses, of which ref. 119 is representa-
tive. The antinociceptive effect of (-)-epibati-
All substitutions on the pyrrolidine ring di- dine is antagonized by pretreatment with
minished the binding affinity compared with mecamylamine (120) (a ganglionic blocking
that of compound (69). The primary metabo- agent), but not by naloxone (121) nor, surpris-
lism of compound (69) involves oxidation at ingly, by hexamethonium (122). It is estab-
the 5'-position. It was therefore unexpected lished (120,121) that epibatidine is a nicotinic
that the 5'-methyl congener of compound (69) receptor agonist. Both enantiomers of epibati-
has in vitro half lives equivalent to or shorter dine I(+)-epibatidine is synthetic] had potent
than those of (69) itself. antinociceptive activity (121), and the only
Nicotine decelerates aging of nigrostriatal central receptors at which potent affinity
dopaminergic neurons (8) and it has been sug- was found were nicotinic. Epibatidine did not
gested that nicotine may relieve the symptoms bind to p, K , or 6 analgesic receptors, nor to
of Parkinson's disease (7). muscarinic or 5-HT, receptors. There was no
5-Ethynylnicotine (70) was designed as a significant binding to adenosine, adrenergic,
potential anti-Parkinsonian agent (9). dopaminergic, GABA, substance P, chole-
This compound was more potent than nic- cystokinin, NMDA, or u receptors (121). Epi-
otine in releasing dopamine from rat striatal batidine has very high affinity for the major
slices. The (S)-compoundwas the more potent nicotinic subtype in the brain, a& (123).
4 Cholinergics Not Closely Related Structurally to Acetylcholine 53

However, the alkaloid is nonselective in its ac- positions 5 or 6 in the 3-pyridyl fragment are
tions on nicotinic receptors, including the gan- potent nicotinic receptor ligands (126).
glionic (a3&) and neuromuscular (a1P18y~)
subtypes, as a consequence of which there is a
very narrow therapeutic index between bene-
ficial analgesic actions and toxic and ulti-
mately lethal actions on the cardiorespiratory
system. Replacement of the chlorine atom of
(+)-epibatidinewith hydrogen resulted in re-
tention of comparable affinity for nicotinic
sites, whereas replacement with methyl or io-
dine lowered affinity (118).
ABT-594 (721, described as an azetidine
bioisostere of nicotine with the (Rbabsolute

These as well as the 2-fluoro analog possess

subnanomolar affinity for the receptors in rat
forebrain. The 5-iodo compound showed the
highest affinity, comparable to that of epibati-
configuration, retains analgesic actions while dine. Additional 3-pyridyl ether congeners of
showing areduced propensity toward the toxic (73)/(74)have been cited from the patent lit-
side effects seen with epibatidine (123). erature (109); some of these bind with high
ABT-594 was approximately 70 times more affinity to 3H-cytisine and 3H-epibatidine
potent than morphine in a spectrum of acute sites, but exhibit much lower aMinity for 1251-
and chronic nociceptive models, and unlike bungarotoxin sites. Compound (751, the
morphine, it showed no evidence of tolerance 2-methyl congener of (741, was described (127)
or opioid-like dependence liability, nor did it as a nicotinic receptor ligand for receptor sub-
show effects on respiration or gastrointestinal types having mainly a, and P2 subunits. It
motility. It is said (113) not to demonstrate the showed positive effects in rodent and primate
addictive effects of nicotine. The (5')-enantio- models of cognitive enhancement, and a re-
mer of ABT-594 also showed potent analgesic duced propensity (compared to nicotine) to ac-
activity and, like the (R)-enantiomer, it was tivate peripheral ganglionic-like nicotinic re-
active after intraperitoneal or oral adminis- ceptors and to elicit seizures.
tration (124). Structure-activity studies sug-
gested that the N-unsubstituted azetidine
moiety and the 2-chloro substituent on the
pyridine ring are important contributors to
the potent analgesic activity. The deschloro
compounds (73) and (74) possess subnanomo-
lar affinity for brain nicotinic receptors (125),
but no analgesic testing data were reported for
these compounds. Computational studies indi-
cated that a reasonable superimposition of a A series of pyridine-based nicotine conge-
low energy conformer of (73) with (S)-nicotine ners (76-80) in which R, and R, were H or a
and (-)-epibatidine can be achieved. Further, variety of substituents was subjected to 3D-
it was concluded that the optimal internitro- QSAR analysis of their ability to bind to cen-
gen distance for binding of these types of com- tral a$, receptors (128).
pounds to nicotinic receptor(s) is 5.5 A. Deriv- Bulky substituents at the 6-position of the
atives of (73) having a halogen atom at pyridine ring reduce the affinity of the com-

(109) to bind tightly to 3H-nicotine receptors

in rat cerebrum and to induce calcium flux
through a4P2receptors with potency compa-
rable to that of nicotine.
DBO-83 (86) showed powerful affinity for
a$, nicotinic receptors, and it demonstrated
antinociceptive activity (123).
In a series of substituted 3,8-diazabi-
cycloL3.2.lloctane derivatives, described as
structurally related to epibatidine (131), the
most interesting was (87). This compound
showed analgesic properties after subcutane-
pounds, whereas bulky ring systems including ous injection, which were reversed by
an sp3 nitrogen increase the affinity of the mecamylamine but not by naloxone. It had
compounds, consistent with results reported high affinity for binding at the a,& nicotinic
earlier by Glennon et al. (129). subtype, but it had no effect at the myoneural
A series of pyridyl ethers, typified by (81) junction. The S-(-)-spiro compound (88)is a
and (82),exhibited high binding affinity at 3H- potent full agonist in vitro at the rat a, nico-
cytisine rat forebrain sites (cytisine is a nico- tinic receptor (132); it is highly selective over
tinic receptor partial agonist), but only mod- the a subtype. However, even minor
erate affinity at 3H-epibatidine sites (109, changes in structure result in significant loss
130). in a, affinity. A synthetic analog (89) of the
A group of thio ethers (831, (84), (851, re- marine worm toxin anabaseine (90) is "func-
ported from the patent literature, was stated tionally selective" for the a, nicotinic receptor
4 Cholinergics Not Closely Related Structurally to Acetylcholine 55


(133). The structural dissimilarity between

the two a, receptor stimulants (88)and (89)is
The phenylisoxazole (91)showed moderate
binding aMinity to 3H-cytisinebinding sites in

rat cortex, but it also demonstrated a mark-

edly lower toxicity compared to epibatidine
(109). Antinociceptive activity of this com-
pound was not reported.
Lobeline (92), an alkaloid obtained from
Lobelia inflata, binds with high affinity a t
some nicotinic receptors, and it produces some
(but not all) of the effects of (-)-nicotine (134).
stimulant. However, unlike nicotine, the ini-
tial stimulation is not followed by a dominant
blocking action (137).
Applying an extension of techniques of dis-
tance geometry to analysis of a number of
known nicotinic receptor agonists, Sheridan
et al. (138) proposed a definition of the nico-
tinic agonist pharmacophore, the essential
features of which were proposed to be: A, a
cationic center; B, an electronegative atom;
Lobeline also demonstrates antinociceptive and C, an atom that forms a dipole with B. It
effects, but these are complex (135): they are was concluded that there is only one arrange-
observed after intrathecal but not after subcu- ment possible for superimposition of these es-
taneous administration. Subcutaneous ad- sential groups: a triangle having dimensions
ministration of lobeline enhanced nicotine-in- A-B (4.8 A), A-C (4.0 A), and B-C (1.2 A). f i r -
duced antinociception in a dose dependent ther consideration of this proposed nicotinic
manner. Removal of one or both oxygen func- agonist pharmacophore by computational
tions from lobeline permits retention of the chemical studies of nicotine, epibatidine, and a
analgesic potency and activity of lobeline itself series of oxazolyl-azabicycloalkanes (139) led
(134). Moreover, removal of one or both oxy- to the conclusion that future modeling of nic-
gens diminishes, by at least 25 times, the af- otinic agonists should utilize the global energy
finity for nicotinic receptor(s) in rat brain ho- mimimum of epibatidine as the reference
mogenates. It was concluded that there is no structure, in which the torsion angle r = rl"
direct relationship between neuronal nicotinic (structure 95).
receptor (primarily a,& type) affinity and an-
algesia as measured by the tail-flick assay.
(+)-Anatoxin-A (93), produced by a fresh
water cyanobacterium, is more potent than
nicotine or acetylcholine in stimulation of
some subpopulations of nicotinic receptors
(136). The compound also stimulates release
of acetylcholine from hippocampal synapto-
With resped to the oxazolylazabicycloodanes
(structure 96), the optimum a-b distance was
concluded to be 7-8 Additionally, it was con-
cluded that the receptor area is sensitive to
changes in steric bulk and electrostatic potential
in the aliphatic area around the sp3 nitrogen.
Numerous nicotinic ligands interact with
muscarinic acetylcholine receptors, and vice
versa (109). Compounds (97) and (98) are ex-
amples of this varying selectivity: the nico-
1,l-Dimethyl-4-phenylpiperazinium (DMPP) tinic/muscarinic selectivity ratio in these sys-
(94), like nicotine, is an autonomic ganglion tems depends on the size of the substitution on
4 Cholinergics Not Closely Related Structurally to Acetylcholine

(3)is almost inert, as are both enantiomers of

the other three diastereomers of structure
(99) (epimuscarine, allomuscarine, and epial-
lomuscarine) (141). A point of interest is the
absolute configurational identity of the C2 PA-
sition of muscarine (3) and of the S-(+)-eu-
tomer of acetyl p-methylcholine (101).

The oxidation product of (+)-(2S,3R,5S)-

muscarine, muscarone (102), shows even
more structural analogy to the acetylcholine
the hydrogen bond acceptor geometrically op-
posite to the cationic moiety. Smaller substi-
tutions favor nicotinic binding, whereas larger
substitutions favor muscarinic binding (140).
Additional recent advances in nicotinic mo-
lecular design and therapies are reviewed in
Ref. 109.

4.2 Muscarine, Muscarone, and Related

molecule; it is an active muscarinic agonist,
and it also exhibits a nicotinic component of
The muscarine molecule (3)may be viewed as activity not possessed by muscarine.
a cyclic analog of acetylcholine in which the For many years, the literature (e.g., Ref.
carbonyl and /3-carbons are linked by a bi- 142) consistently presented misleading andlor
methylene bridge (cf. structures 99 and 100). incorrect information concerning the stereo-
chemistry of the muscarone molecule, and
there were accompanying hypotheses, based
on this misinformation, rationalizing the
seemingly confusing relationship of the abso-
lute configuration of muscarone enantiomers
to their pharmacological properties. This con-
fusion was resolved by the proof (143)that the
eutomer of muscarone has chirality at C2 and
C5 (2S, 5 s ) identical with natural muscarine.
Naturally occurring (+)-muscarine is one The earlier literature (141,144) had reported
of eight stereoisomers of structure (99).The small eudismic ratios (2.4-10.1) for the mus-
(-)-enantiomer of (+)-(2S,3R, 5s)-muscarine carone enantiomers, in contrast to the large

values established for muscarine enantio-

mers. This pharmacological inconsistency has
been explained by De Amici and coworkers
(145) on the basis of optical heterogeneity of
the muscarone enantiomers used in the ear-
lier studies. These workers performed enan-
tiospecific syntheses to obtain the two musca-
rone enantiomers in >98% enantiomeric
excess. In both binding and functional studies,
(-)-(2S, 5s)-muscarone was the eutomer, and
the eudismic ratios of the muscarone enanti-
omers were in the range of 280-440, which
are quantitatively similar to those for musca-
Enantiomerically pure 4-deoxy-4-fluoro- the C2 methyl of compound (106) to ethyl
muscarines have been reported (146). The (148) or replacing the C2 methyl with hydro-
most active member of the series was the gen (41). The data on these furan derivatives
2S,4R,5S-enantiomer (103), whose pharma- are consistent with the rule of five.
cology is much like that of muscarine itself, Muscarinic activity of 2-methyl-4-trimeth-
except that the fluoro compound showed a one ylammoniummethyl-1,3-dioxolane(107) re-
order of magnitude increase in affinity for car- sides in the cis isomer (149); stereospecific
diac M, receptors (those controlling rate). synthesis of the two enantiomers of the cis
isomer revealed that the L-(+) enantiomer

Beckett and coworkers (147) reported the (C4 = R ) is more than 100 times more potent
approximate equivalence of muscarinic action than the D-(-) enantiomer (C4 = S), and is
shown by enantiomers of 4,5-dehydromusca- approximately six times more potent than ace-
rone (104). tylcholine in a guinea pig ileum assay. The
more active L-(+) compound is related config-
urationally to the most potent muscarine ste-
reoisomer (3),although it should be noted that
several authors in the older literature incor-
rectly assigned the S absolute configuration to
position 4 of the L-(+)-cis compound (1071,
apparently through misapplication of priority
rules. 2,2-Dialkyl analogs of these dioxolanes
are much weaker muscarinic agonists than
dl-Dehydromuscarine (105)retains consid- the parent systems (107), and the difference
erable muscarinic agonist activity, but it in potency between the C4 R and S enan-
shows no effects at nicotinic receptors (141). tiomers diminishes sharply with increasing
Incorporation of the elements of the musca- size of substituents at C2 (150). Both enantio-
rine structure into an aromatic ring has pro- mers of the cis- and trans-oxathiolane system
duced some systems, such as compound (1061, (lOS), bioisosteres of the dioxolanes, were
which approach acetylcholine in muscarinic evaluated for nicotinic and muscarinic effects
potency (41). Activity is lowered by changing (151).
4 Cholinergics Not Closely Related Structurally to Acetylcholine 59

lective muscarinic agent with a large eudismic

ratio (152). (Note that the presence of the sul-
fur atom reverses the R,S designations of the
chiral centers, compared with muscarine.)
Compound (110) is exponentially less po-
tent than (111)at muscarinic receptors. Both
compounds demonstrate low nicotinic potency
The (+)-cis isomer of (108) was the most and activity. The sulfone congeners (112) of
potent muscarinic of the series. It demon- the enantiomers (2R,5R and 2S,5S) of the cis-
strated a eudismic ratio of the same high order structure are weak muscarinics with a eudis-
of magnitude as that for muscarine and the mic ratios of unity.
dioxolanes. This (+)-cis enantiomer has the
same absolute configuration as the muscarini-
cally most active L-(+)-muscarine (2) and the
(+)-cis-dioxolane (109). The other isomers
represented by structure (1081, although
much less potent than the (+)-cis isomer, also
demonstrated a degree of muscarinic agonist
effect. All four isomers of structure (108)
showed similar nicotinic potency and activity,
close to that of carbamyl choline, and eudismic Neither is an extremely potent nicotinic,
ratios were small. although the 2R,5R enantiomer is more po-
tent than the 2S,5S.
The cis and trans isomeric mixtures of di-
oxolane congeners bearing sulfur, phospho-
rus, or arsenic cationic heads (113-115) dis-
play lower muscarinic effects than the
corresponding nitrogen system (153).

Studies of the diastereomeric cis-sulfox-

ides (110) (2R,3S,5R) and (111)(2R,3R,W
indicated that compound (Ill), which has H3C CH2-X

H3CA0%H2--h(CH3)3 Both of the racemic cis-1- and cis-3-des-

etherdioxolane compounds (116 and 117)
(110) demonstrate muscarinic activity not substan-

the same absolute configuration as (+I-

H3C * 0ACH2-N(CH3)3

(2S,3R,SS)-muscarine (3),is a potent and se- (117)


tially lower than that of the "supermusca-

rinic" L-(+)-cis-dioxolane (109) (153). It was
suggested (154) that occupation of only one of
the two receptor subsites proposed to be react-
ing with the ring oxygens of the cis-dioxolane
(109) is sufficient to induce muscarinic activ-
The moderately high potency (1110 acetyl-
choline) of the spirodioxolane (118)compared
with the low muscarinic potency (11300 acetyl-
choline) of a mixture of isomers of a more flex-
ible system (119), led Ridley and coworkers
(155) to speculate that the three-dimensional
geometry imposed by the molecular rigidity of
compound (118) may approximate the shape
of the L-(+)-cis-dioxolane (109) when it binds
to muscarinic receptor(s).

A more complex spirodioxolane molecule

(120), bearing a tertiary arnine rather than a
quaternary moiety, was resolved (156). The
3R,2'S isomer (121) was more potent in bind-
ing studies, but the 3R,2'R isomer (122) dis-
played larger selectivity between MI receptors
(ganglion) and M, receptors (heart). Additional 1,2,4-oxadiazole derivatives
The 3R stereochemistry of the most potent containing 1-azanorbornane (124a and 124b)
isomers (121) and (122) is consistent with and isoquinuclidine (125) rings were studied
that of other potent l,3-dioxolane derivatives. (158). These compounds can exist as geomet-
Extension of these studies (157) led to a race- ric isomers, and the exo-1-azanorbornane iso-
mic 1,2,4-oxadiazolederivative (123) that has mer (124b) was described as one of the most
high affinity and efficacy at central muscarinic potent and efficaceous muscarinic agonists
receptors. known.
4 Cholinergics Not Closely Related Structurally to Acetylcholine 61

muscarone may not play a critical role in ago-

nist-muscarinic receptor interactions. Beckett
and coworkers (147) had suggested the prime
importance of the keto group of muscarone
(compared with the ring oxygen), and the im-
portance of the ring C-methyl group has been
cited previously.
Certain cyclohexane analogs of desether-
muscarine and desethermuscarone showed
greatly diminished muscarinic activity (164).
These compounds, however, lacked the pre-
sumably important ring C-methyl group.

4.3 Pilocarpine and Analogs and Congeners

Pilocarpine (128), the chief alkaloid from the
leaflets of shrubs of the genus Pilocarpus, has
a dominant muscarinic action, but it causes

A carbocyclic muscarine analog, (+)-des-

ethermuscarine (1261, exhibits striking mus-
carinic effects (1591, although the compound

anomalous cardiovascular responses, and the

sweat glands are particularly sensitive to the
drug (165).
Its structure is distinguished by the lack of
a quaternary ammonium head; however it is
is considerably less potent than was originally presumed that a nitrogen-protonated cation is
reported (160). The other three stereoisomers the biologically active species. Pilocarpine has
of desethermuscarine (epi-, allo-, and epiallo-) been described as a muscarinic partial agonist
are weaker cholinergic agents (161,162). Two (166). Structural and conformational analo-
attempts (159, 163) to obtain (2)-desether- gies and interatomic distance similarities be-
muscarone (127) resulted in inseparable mix- tween pilocarpine and muscarinic agonists
such as acetylcholine, acetyl P-methylcholine,
muscarine, and muscarone have been invoked
(167) to rationalize pilocarpine's pharmaco-
logic properties. The potential utility of pilo-
carpine in treatment of glaucoma is limited by
its low ocular bioavailability. A double pro-
drug strategy (168, 169) involves hydrolytic
cleavage of the lactone ring of pilocarpine and
esterification of the freed carboxyl and alcohol
tures of epimers, which were reported (159) to groups (129) to produce derivatives with a
be equipotent to acetylcholine in assays for greatly enhanced lipophilic character. In the
nicotinic and muscarinic effects. The high po- presence of human plasma or rabbit eye ho-
tencies of desethermuscarine (126) and of the mogenates, pilocarpine was reformed from
mixture of desethermuscarone epimers sug- these derivatives in quantitative amounts be-
gest that the ring oxygens in muscarine and cause of the action of tissue esterases.

Cyclic carbamate analogs (130-132) of pi-

locarpine were designed (170) to extend pilo-
carpine's duration of action, which is a reflec-
tion of its metabolic inactivation by hydrolytic
cleavage of the lactone ring.
of arecoline) varies with the nature of the al-
cohol: from the methyl ester (133a) to the
ethyl (133b), the affinity for the muscarinic
receptor(s) increases (175), but there is a
sharp drop in affinity and intrinsic activity
with the n-propyl ester (133~). However, the
ally1 ester (133d) is more potent and active
than the n-propyl (although less potent than
the assay's reference standard compound, car-
bamyl choline); the propargyl ester (133e)is
more active than carbamyl choline and indeed
was described (175) as a more potent musca-
rinic agonist than acetylcholine. Data were
presented suggesting that the triple bond of
Analog (130),having the same substitution the propargyl ester contributes to recept,or
pattern as pilocarpine,was equipotent to pilo- binding. Reduction of the ring double bond in
carpine in a guinea pig ileum assay. In vitro, the methyl (133a) (arecoline) and ethyl
base-catalyzed epimerization of pilocarpine at (133b) esters of arecaidine causes a 250 to
the C-ethyl group position forms the diaste- 1000 times reduction in muscarinic receptor
reomer isopilocarpine in which pharmacologic affinity.
activity is lost (171). The ester group positional isomer (134) is
less potent and less active than arecoline in
4.4 Arecoline and Analogs and Congeners the guinea pig ileum assay (1761, and the N,N-
Arecoline (133a),an alkaloidal constituent of dimethyl quaternary derivative of (134) is
the seeds of Areca catechu, is a cyclic "reverse slightly more potent than the tertiary amine.
ester" bioisostere of acetylcholine (cf. com-
pound 22).
In contrast to pilocarpine, arecoline acts at
nicotinic receptors as well as at muscarinic
sites; it has been described (172) as a partial
agonist at MI and M, receptors. Arecoline is
equipotent to its quaternary analog, N-meth-
ylarecoline, as a muscarinic agonist (172). The
secondary amine, norarecoline, is a somewhat
weaker muscarinic agonist than arecoline
(173,174).The muscarinic activity of esters of
arecaidine (the free carboxylic acid derivative
4 Cholinergics Not Closely Related Structurally to Acetylcholine

The five-membered ring congener (135)of

arecoline is approximately 50% as muscarini-
cally potent as arecoline in a guinea pig ileum
assay, and the five-membered ring analog

(136)of dihydroarecoline is approximately 1% I
as potent as arecoline in this assay (175). The
sulfur bioisostere (137)of arecoline (R = CHJ
is more potent and active than its N,N-di-
methyl quaternary ammonium congener, be-
ing approximately equipotent to arecoline it-
self (176).The ester group positional isomer of
the sulfur bioisostere (138)(R = CH,) retains
muscarinic effects, but it is somewhat less po-
tent and less active than the &substituted
compound (137). In both (137) and (138)the
ethyl and n-propyl esters are inferior to the It was proposed that the amidine moiety of
methyl. the tetrahydropyrimidine ring would be a suit-
able ammonium bioisostere, lacking the per-
manent cationic head present in a quaternary
ammonium system. This might facilitate pen-
etration of the blood-brain barrier. Of this se-
ries, the methyl ester (139a)shows high a n -
ity for muscarinic receptors in rat brain, and it
stimulates phosphoinositide metabolism in
the rat hippocampus. It ameliorated memory
deficits associated with lesions in the septohip-
pocampal cholinergic system in rats. In a sub-
sequent communication (178) it was reported
that compounds (139b), (139e), (1401, and
(141) exhibited marked functional selectivity
for MI vs. M, receptors.
The potential utility of arecoline in produc-
ing significant cognitive improvement in Alz-
heimer patients (179) and in enhancing learn-
ing in normal young humans and in aged
nonhuman primates (180, 181) is largely ne-
gated by its short duration of action, which has
Further application of the bioisosterism been ascribed (182) to rapid in vivo hydrolysis
strategy replaced the tetrahydropyridine ring of the ester group. This metabolic lability
of arecoline with tetrahydropyrimidine stimulated preparation of metabolically stable
(139a-e) (177). aldoxime derivatives (142) (183); compounds

posed to demonstrate a separation of CNS

from peripheral effects. Structural variations
based on (144) in which R' = CH, and the R
group is such that the carbonyl moiety is a



part of a carbonate, carbamate, or carboxylate

ester provided compounds having little or no
muscarinic activity. Some of the carbamate
derivatives demonstrated in vitro cholinester-
ase inhibitory activity (184).
were prepared in which R and R' = alkyl, cy-
Both enantiomers of the reversed ester
cloalkyl, olefinic, or acetylenic groups.
congener (145) of arecoline are (approxi-
Derivatives of structure (142) in which R =
mately equally) weak muscarinic agonists
CH, and R' = CH, or propargyl are musca-
(175),as are their N-methyl quaternary deriv-
rinic agonists, both in vivo and in vitro. These
compounds are two to three orders of magni-
tude more potent than arecoline, and they
have a longer duration of action. They are
orally effective. A large number of carbamate
derivatives (143), where R = aryl or alkyl,
were prepared as possible prodrugs to the al-
doximes (142). The derivative where R = p-
chlorophenyl had high potency and activity
(181); it was more active in an assay for CNS
effect than in an assay for peripheral cholin-
ergic effect. Thus, this compound was pro-
4 Cholinergics Not Closely Related Structurally to Acetylcholine

Ketoxime ethers derived from structures

(146)and (147) where R = H, methyl, propar-
gyl, or C-alkyl-substituted propargyl showed
M, agonist activity in a rat aorta preparation,
but no M, agonist activity (185).

All four isomers of the thianium system

(150) have been prepared and studied (175).
The sulfur atom in sulfonium salts may form a
chiral center, and the stereoisomers can be
isolated, given that the energy barrier to pyra-
midal inversion is substantially higher (- 100
kJ/mol) than it is in the case of the correspond-
ing ammonium compounds (-38 kJ/mol). The
(+ )-trans-thianium isomer (150) demon-
strated high muscarinic potency, slightly
higher than that of the S-quinuclidine (149),
but the (-)-trans-enantiomer (150) and the
(?)-&isomer (150) demonstrated low po-
tency. These data on the piperidine, quinucli-
dine, and thianium derivatives were rational-
ized (175) on conformational bases.

Modification of the aldoxime ether group

by introduction of an electron withdrawing
moiety led to the finding (186) that the Z-N-
methoxyimidoyl nitrile group serves as a sta-
ble methyl ester bioisostere. An example of
this molecular modification, compound (1481,

In an alternate strategy to provide resis-

tance to in vivo ester cleavage of arecoline
(187), bioisosteric replacement of the methyl
ester groups of arecoline and norarecoline by a
3-alkyl-1,2,4-oxadiazole ring (151)was inves-
tigated (188).
Analogs of structure (151),where R = un-
is a functionally selective Ml partial agonist branched Cl-, alkyl, are muscarinic agonists,
for which potential utility in treatment of Alz- and most of these show strong affinity in two
heimer's syndrome was suggested. binding assays in rat brain membranes. Deriv-
In contrast to the enantiomers of (1451, atives of structure (151), in which R = a
both enantiomers of 3-acetoxyquinuclidine branched alkyl chain or a cyclic system, are
(aceclidine, 149) are potent muscarinics, and muscarinic antagonists. Analogs in which the
the S-enantiomer is only approximately one R group contains an ether moiety (e.g., CH,-
order of magnitude less potent than acetylcho- 0-CH,) are also muscarinic agonists, but they
line. have lower receptor binding affinity than the

alkyl derivatives. Congeners of (151)in which

the 1,2,5,6-tetrahydropyridinering was re-
placed by quinuclidine or tropane, are potent
antagonists with high affinity for central mus-
carinic receptors. Introduction of a methyl
substituent at position 5 or 6 of the tetrahy-
dropyridine ring of (151) (R = n-C,H,) de-
stroyed agonist effect and produced a musca-
rinic antagonist in the single example
reported. The N-desmethyl analog of (1511,
where R = n-butyl, retains potent muscarinic
agonism. Additional members of the series of
derivatives of (151)have been reported (1891,
and molecular mechanics calculations indi-
cated a preference for the E rotameric form
In continuation of efforts to identify MI-
selective muscarinic agonists capable of cross-
ing the blood-brain barrier, the 3-carbo-
methoxy group of arecoline was replaced by
bioisosteric 1,2,5-oxadiazole(154) or by 1,2,5-
thiadiazole rings with oxygen ether substitu-
ents at position 3 (155)or with thioether sub-
stituents at position 3 (156) (190). muscarinic receptors. However, all members
The ring-oxygen bioisosteres (154) (R = n- of the thiadiazole oxygen ether series (155),
butyl or n-hexyl) show low affinity for central where R varied from CH, through n-C,H,,

E Rotamer Z Rotamer
4 Cholinergics Not Closely Related Structurally to Acetylcholine 67

and also included some branched chain C, al- antinociceptive effects from undesirable mus-
kyl groups, demonstrated high potency in dis- carinic side effects (salivation, tremors).
placing tritiated oxotremorine-M (a nonse- These efforts were unsuccessful. As a result of
lective muscarinic agonist) and tritiated a concurrent study of rigid, conformationally
pirenzepine (a selective M, antagonist) from restricted analogs of (156), it was proposed
rat brain membrane tissue. The n-butyloxy that the biologically active conformation of
and n-pentyloxy substituents provided maxi- (156) has a torsion angle T C3-C4-C3'-N2'
mal pharmacological effects. A subsequent "close to 180°."
communication (191) reported that a deriva- Study of a series of arecoline congeners
tive of (155) in which R = n-hexyl (xanome- (158)in which the carbomethoxy group is re-
line) is an M, agonist with potential value in placed by a pyrazine moiety (R = CH,-
treatment of Alzheimer's syndrome. The pri- C,H,,) revealed that M, agonist activity is re-
mary site of oxidative metabolism of xanome- lated to chain length, with n-hexyl providing
line is the hexyloxy side chain (192), and a maximum activity (195). A comparison of MI
secondary metabolic process involves N-de- agonist efficacy of these pyrazines and related
methylation. To prevent this oxidative N-de- 1,2,5-thiadiazoles (155)and 1,2,5-oxadiazoles
methylation, the N-methyl group was incorpo- (154) suggested that M, efficacy may be re-
rated into a series of azabicyclic and tricyclic lated to the magnitude of electrostatic poten-
systems, illustrated by (159)and (160). tial located over the nitrogens of the respec-
Some members of the series exhibited se- tive heterocycles. The heteroatom directly
lectivity for M, receptor binding. The alkyl- attached to the 3 position of the pyrazine or of
thio analogs (156) demonstrated a similar the 1,2,5-thiadiazole markedly influences the
structure-activity relationship to the alkoxy M, efficacy of the compounds by determining
series (155); however, the thio ethers have the energetically favorable conformers for ro-
higher receptor affinity and higher potency. tation about the bond connecting the tetrahy-
Thus, these systems (155) and (156) show a dropyridyl ring and the heterocycle. A three-
higher degree of selectivity for M, receptors dimensional model for the M, agonist
than for M,. The unsubstituted system (157) pharmacophore was proposed as a result of
(R = H) is a potent but nonselective musca- these studies.
rinic agonist. Derivatives of (1571, where R =
n-propyl, n-pentyl, n-heptyl, or n-octyl, have
10 to 100 times less affinity for central musca-
rink receptors than the corresponding alkoxy
and alkylthio derivatives.

Compound (156)was reported (193) to be a

potent antinociceptive agent, but there was
little difference between an analgesic dose and
one producing salivation. Analogs of (156)
were prepared (194) in attempts to separate

The tetrahydropyridine ring was fused

with a 3-alkoxyisoxazole moiety in a series of
compounds (161a-g)(174). Both (161a)and

&T OR'

Another tetrahydroazepine congener (163)

displays higher affinity for muscarinic recep-
tors but somewhat lower efficacy than the
analogous fused piperidine compounds (161)
(197); it was described as a partial agonist.
Studies (198)of sulfur analogs and congeners
(164-167) of the isoxazolotetrahydropyri-

(161b)are muscarinic agonists in a guinea pig

ileum assay, and as with arecoline and
norarecoline, the N-methyl tertiary amine
congener (161a)is somewhat more potent
than the nor derivative (161b).
Variation of the 0-alkyl (R') group in the
nor series (l6lb-g) produced pharmacologi-
cal activities and potencies parallel to those
described for the esters of arecaidine (113a-
el: the 0-n-propyl and n-butyl homologs
(161d)and (161e1,respectively, demonstrate
only weak muscarinic agonist effect; however,
the 0-ally1 and propargyl homologs displayed
prominent muscarinic agonism, with the 0-
propargyl compound being one order of mag-
nitude more potent that the 0-allyl. However,
there is no apparent correlation between the dines (161)demonstrated that the thiapyran
derivatives (164) and (165) are inactive as
effects of the compounds on central and pe-
muscarinic agonists. However, the S-methyl
ripheral cholinergic receptors. It was specu-
lated (174) that the effects observed in the il- sulfonium derivative (167a)binds to brain
eum preparation are mediated primarily by and heart muscarinic receptors, albeit not as
M, receptors, whereas the rat brain mem- strongly as arecoline. Compound (167a)is
brane-binding data may represent a nonde-
scriminate binding to all types of muscarinic
binding sites.
The tetrahydroazepine congener (162) of
the tetrahydropyridine isoxazole systems
(161) is said to possess high affinity for the
central MI receptor, coupled with only limited
toxicity (196).
4 Cholinergics Not Closely Related Structurally to Acetylcholine

also inferior in potency and activity to "sul-

foarecoline" (137). However, the numerically
large ratio of agonist activity at M, receptors
to that at M, receptors for compound (167a) is
slightly greater than for arecoline or sul-
foarecoline, which is a desirable parameter for
therapy of Alzheimer's disease. The 0-ethyl
homolog (16%) is a muscarinic antagonist, in
contrast to its tetrahydropyridine bioisostere
(16lc),which is described as a muscarinic par-
tial agonist (198). The 0-isopropyl-S-methyl
(167~) and 0-propargyl-S-methyl(167d)sul-
fonium homologs demonstrate pharmacologi-
cal properties similar to those of the 0-methyl
homolog (167a). The single structure (166a)
derivative tested was a weak muscarinic ago-
nist in all assays, but it demonstrated a de-
cided preference for M, receptors over M, re-
olism in rat cortex and hippocampus. Increas-
ing the length of the alkyl substituents
(168b-h) increased the affinity for musca-
rinic receptors, albeit not in a linear fashion,
yet decreased activity in the phosphoinositide
turnover assay. It was concluded that at low
concentrations, compound (168a) selectively
stimulates M, receptors.
Regioisomers of an exocyclic amidine sys-
tem (169a-d) bioisosteric with arecoline were
tested as their racemic modifications (200).

Further modification of the arecoline struc-

ture involved replacement of the ester group Only the 5-carbomethoxy isomer ( 1 6 9 ~ )
of tetrahydropyrimidine derivatives (as in displayed high affinity and activity at musca-
structures 139a-f) with a 1,2,4-oxadiazole rinic receptors coupled to phosphoinositide
ring (structures 168a-h) (199). metabolism in rat cortex. Evaluation of other
Each of the test com~ounds
* (168a-h) alkyl esters (170a-c) of the 5-carboxylic acid
bound with high afiinity to muscarinic recep- revealed that only the propargyl derivative
tors from rat brain. The &methyl homolog (170c) retained substantial agonist activity.
(168a) displayed high efficacy at muscarinic In a series of cyclic guanidines, (2-amino-
receptors coupled to phosphoinositide metab- tetrahydro-pyrimidines, 171a-e), all mem-

ity in rat cortex (201); compounds (173a and

(173b) (spiro-4-piperidine derivatives) showed
marked muscarinic agonist effects in a phos-
bers showed high binding affinities in a rat
phatidyl inositol turnover assay. Compounds
brain membrane assay (200). However, only
(173a) and (173b) also showed moderate bind-
the methyl and propargyl esters (171a and
ing ability against [3Hl-N-methylscopolamine
171d) showed high muscarinic agonist activ-
and [3H]oxotremorinein rat cortex tissue. Com-
ity in a phosphoinositide metabolism assay.
pound (173a) compared favorably with areco-
Computational chemical studies revealed a
line in terms of receptor efficacy although it, like
common minimum energy conformation for
(173b), demonstrated much lower receptor af-
all of the muscarinically active members of
finity. The 2-ethyl homolog ( 1 7 3 ~ )demon-
several series (169, 170, 139, and 171),which
strated decidedly lower receptor efficacy than
suggests that all of the subject compounds in
(172a) or (172b), and it also demonstrated
this study interact with muscarinic receptors
lower receptor affinity. Variations of structure
in a similar fashion. The utility of amidine sys-
(173)are represented by (174) and (175),which
tems as suitable replacements for the quater-
are agonists at rat central MI receptors (202).
nary ammonium group of acetylcholine in de-
signing ligands for MI receptors is suggested
by the results of these studies.

Studies of extended series of other spiropi-

peridine derivatives demonstrated that com-
pound (176) is a partial muscarinic agonist
The spiropiperidine systems (172a, 172b) that reverses carbon dioxide-induced impair-
(diastereomers, stereochemistry unspecified) ment in mice (203), and that compound (177)
are hybrids of the arecoline molecule and of is a muscarinic agonist with an affinity for cor-
the spirodioxolanes (121 and 122). tical M, receptors (204). The (2)-spiroquinu-
Compounds (172a) and (172b) (spiro-&pi- clidine derivative (178) is a selective M, ago-
peridine derivatives) show weak binding abil- nist (205).
4 Cholinergics Not Closely Related Structurally to Acetylcholine

which is approximately equipotent to acetyl-

choline as a muscarinic agent but lacks nico-
tinic effects (213).
As with pilocarpine and arecoline, in-
creased interest in pharmacotherapy of Alz-
heimer's disease and other memory deficit
conditions has led to renewed and expanded
studies of oxotremorine. This compound has
Some quinuclidine and azabornane deriva- little or no effect on serum or red cell butyryl-
tives bearing oximino or heterocyclic ring sub- cholinesterase. Oxotremorine has been de-
stituents at position 3 (e.g., 179 and 180) dem- scribed as a potent muscarinic partial agonist
onstrate potent muscarinic agonism. Some (172). However, an earlier report (11) pre-
compounds of these types are selective for M, sented evidence that oxotremorine has an in-
and M, receptors (206-210). direct action in the CNS, perhaps by stimula-
tion of choline acetyltransferase, resulting in
4.5 Oxotremorine and Analogs and
elevation of acetylcholine levels. The periph-
eral actions of oxotremorine, including effects
Tremorine (lsl),a synthetic compound with on cardiovascular mechanisms, have been as-
weak cholinergic activity (211, 212) is metab- cribed (172) to preferential activation of M,
olized to the lactam oxotremorine (182), receptors. Brimblecomb (211, 212) reported
72 Cholinergics

pharmacological data on a large number of To assess the validity of conclusion 2 above,

tremorine-oxotremorine derivatives, from Brimblecomb (211) compared the trimethyl-
which the following conclusions were drawn. ammonium quaternary moiety with the l-pyr-
rolidino group in a series of compounds (Table
1. The carbonyl group of oxotremorine is 2.3).
essential. Variations are apparent in the activities of
2. The pyrrolidine nitrogen of oxotremorine the quaternary ammonium salts, but the vari-
may be replaced by a trimethylammonium ation is not nearly as great as that demon-
quaternary group ("oxotremorine-M"), but strated by the tertiary amines (pyrrolidines).
replacement with a tertiary amine (di- The Brimblecomb group (214) described an
methylamino or diethylamino) results in additional series of some 23 tremorine-ox-
great loss of activity. otremorine congeners, but none of these com-
3. The acetylenic bond is essential; partial or pounds showed significant muscarinic agonist
complete saturation results in complete effects in the guinea pig ileum or the cat blood
loss of activity. pressure assay.
4. Increase in the size of the lactam ring re- In a series of compounds (183a-c)in which
sults in a change from agonism to the pyrrolidine ring of oxotremorine is re-
antagonism. placed by imidazole, the parent compound

Table 2.3 Muscarinic Activities of Oxotremorine Congeners and Analogs Containing

Trimethylammonium or Pyrrolidino Groups
Muscarinic Activity (isolated guinea pig ileum,
acetylcholine = 1)

Compound R' = N(CH,),

Number R + R' = 1-pyrrolidino

(1) 1.74 1.48

Q 0


(8) CH,COO- 0.47 0.005
4 Cholinergics Not Closely Related Structurally to Ac

(183a) resembles oxotremorine in its musca-

rink efficacy (215);addition of a methyl group
to the imidazole ring (183b)greatly decreased
muscarinic activity (216), whereas addition of
methyl groups to both the imidazole and the
pyrrolidone rings (183~) produced a potent
muscarinic antagonist (215).

I" R

(l83a) R = R' = H
(183b) R = H; R' = CH3
b N

(186) R = H or CH3; R' = H, CH3, CH3C0, or HCO

(183c) R = R' = CH3

Studies (219,220) of methyl group substi-

All members of a series of oxotremorine an- tution into the oxotremorine molecule (com-
alogs (184a-e), in which the pyrrolidone ring pounds (187a-g), all of which were tested as
iscontracted to a p-lactam moiety (217), dem- their racemates) revealed that the 3'-methyl
onstrated uniformly weak cholinergic effects. isomer (187a) has weak muscarinic stimulant
activity in intact mice.

.-+ R'

(184a) R = R' = H; R" = cNC4H8

(184b) R = CH3; R' = H; R" = cNC4H8
( 1 8 4 ~R
) = H; R' = CH3; R" = cNC4H8
(184d) R = H; R' = CH3; R" = N(CH3)2
(184e) R = H; R' = CH3; R" = N(CH3)3

Compound (184a) is the most potent mus-

carinic agonist of the series, being 6 times less
potent than its pyrrolidone congener (182).
Compound (184b) is a weak partial musca- Similarly, the N,N-dimethyl congener
rink agonist; ( 1 8 4 ~is
) a muscarinic antago- (188) displays weak oxotremorine-like activ-
nist; (184d) and (184e) are muscarinic ago- ity. The remaining isomers (187b-g) have
nists, 220 times less potent than (184a). An
N-acetylated piperidine derivative (185)is a
potent muscarinic agonist (40).
Conversion of the pyrrolidone ring of ox-
otremorine and some congeners into an imid-
azolidone ring (186) produces compounds
(generally of low potency) with a variety of
effects at muscarinic receptors (218).
central atropine-like antimuscarinic effects
but only weak peripheral parasympatholytic
Compounds (187d-f), as well as the C1, C 2
dimethyl derivative (1891, were resolved and
6' N-CH2-C-C-CH2-R


(190a) R = N(CH3)2
(190b) R = N(CH3)3


the enantiomers were evaluated (221). Some

compounds are agonists, some are partial ago-
nists, and some are antagonists at muscarinic (191)
sites. In some instances. the eudismic ratio is
large, and in some instances the ratio is rela- Racernic (191) (226), as well as its pure en-
tively small. Structure-activity conclusions antiomers (227),blocks oxotremorine-induced
cannot be drawn from these data. Arnstutz tremors. In other regions of the brain (e.g.,
and coworkers (222) resolved the 5'-methyl those involved in analgesia and hypothermia),
pyrrolidone derivative (187c) as well as the (191) acts as a muscarinic agonist (228). Re-
N,N-dimethyl tertiary amine (190a) and its placement of the acetamido group of (191)
quaternary ammonium derivative (190b). with an oximino moiety and homologation of
The pyrrolidone derivative [(R)-187~1 is a cen- the chain (192) resulted in a fivefold greater
tral and peripheral muscarinic antagonist, as selectivity for M, receptors (229).
has been reported earlier for the racemate.
Compounds (R)-(190a)and (R)-(190b)are po-
tent muscarinic agonists in the guinea pig il-
eum. Compound (R)-(190a) (the tertiary
amine) shows both central muscarinic (hypo-
thermia) and central antimuscarinic activity
(antagonism of oxotremorine-induced tremor)
in vivo. These central agonist-antagonist

properties probably reflect interactions of the (192)

drug with different subpopulations of musca-
rinic receptors. For all three compounds in A series of congeners (193) addressed re-
this study (187c, 190a, 190b), the (R)-enan- placement of the acetamide moiety of com-
tiomers are considerably more potent than the pound (191) by methanesulfonamido, triflu-
(S)-,both in vivo and in vitro, irrespective of oroacetamido, methylsulfonimido,or acetimido;
whether agonist or antagonist effects were introduction of a methyl into the C1 position of
measured. Substitution of a benzene ring into
various positions of the oxotremorine mole- R'\
cule destroys muscarinic stimulant activity; N-CH-C=C-CH2-R"'
these derivatives are competitive muscarinic / I
antagonists (223). The N-methylacetamide
congener (191), closely related to compound (193)
(4) in Table 2.3, was reported (224,225) to be R = CH3S02;CF3CO;CH3C0
a presynaptic antagonist and a postsynaptic R' = CH3;CH3S02;CH3C0
agonist at muscarinic receptors in vitro and in R = H, CH3
vivo. R = 1-pyrrolidyl;N(CH3)2;N(CzH&; +N(CH&
4 Cholinergics Not Closely Related Structurally to Acel

the Qbutyne chain; and variation of the C4 ter- to form a six- or seven-membered ring pre-
tiary amino group or quaternary group (230). served affinity for muscarinic receptor(s), but
Replacement of the acetyl group or the N- abolished efficacy (232).
methyl group in (191) and its analogs by a In a series of oxotremorine and oxotremo-
methansulfonyl group abolishes efficacy and n e (196) analogs (197, 198), all com-
decreases affinity at guinea pig ileal receptors. pounds studied (tertiary and quaternary
The trifluoroacetamide analogs of (191) also amines) demonstrated analgesic effects in
exhibited diminished affinity and efficacy. neurogenic and inflammatory pain models
Substitution of an acetyl group for the (233). It was concluded that these compounds
N-methyl group of (191) decreases efficacy, were acting as muscarinic analgesics. The an-
but has little effect on affinity for the recep- tinociceptive effects were blocked by atropine
tor(~). Most of the tertiary amines showed cen- but not by naloxone or mecamylamine. Mem-
tral antimuscarinic effects. Bioisosteres of bers of the series varied as to classic musca-
(191)bearing a urea moiety (194) in which the rinic agonist effects (e.g., salivation).
R, R', and R"groups were combinations of CH,
and H, displayed muscarinic agonism, partial
agonism, or antagonism (218); a structure-ac-
tivity relationship is not apparent in this se-

A nitrogen mustard congener (199) of ox-

otremorine is a potent and selective musca-
rinic agonist (234).
When (199) was administered to an intact
Conformationally restricted analogs of animal, the signs of muscarinic stimulation
(191)and (195a-i) have been described (231). were followed by a phase of long-lasting anti-
muscarinic effects (235). Both the stirnulatory
and the blocking effects are elicited by the
aziridinium ion (201) formed by in viuo cy-
clization of the parent 2-chloroalkylamine.
This aziridinium system is closely related
structurally to "oxotremorine-M" (196), which
is an extremely potent muscarinic agonist
(212). The blocking activity is correlated with
alkylation (covalent bond formation) of the
muscarinic receptor(s) by the aziridinium ion.
The bromine-derived mustard (200) shows
threefold greater in uitro muscarinic stimu-
lant activity than the chloro compound (1991,
and this can be rationalized on the basis that
bromine is a better leaving group, and aziri-
dinium ion formation is more facile in (200)
These structural modifications resulted in than in (199). Neither of these mustards dis-
decreased affinity for rat cerebral cortex tissue plays a significant amount of effect at nicotinic
and in most cases abolished efficacy at both receptors. These compounds may be useful in
central and peripheral muscarinic receptors. receptor inactivation studies. The slower rate
Other conformationally restricted analogs of of cyclization of the chloro compound (199)
(195) in which the amide moiety and the may permit its penetration of the blood-brain
methyl group on the butynyl chain were joined barrier before formation of the aziridinium
4 Cholinergics Not Closely Related Structurally to Acetylcholine 77

3-5 in Table 2.4) and the pyrrolidinium prod- of compound (203) (239). The (5')-enan-
uct of the 4-halobutylamine moiety of com- tiomers of (204) and (205) exhibit low eudis-
pound (6) in Table 2.4 should be much less mic ratios (1.5 and 4.9, respectively). Com-
susceptible to nucleophilic attack in vivo, and pound (205) has been described (240)as one of
hence these quaternary systems, unlike the the most potent MI-selective agonists (sic)
aziridinium moiety, should have little or no known.
tendency to bond covalently with the musca- Dimethylsulfonium (206a and 206b) and
rinic receptor(s) to produce blockade. Central thiolanium (206c and 206d) analogs of ox-
muscarinic effects (tremors, analgesia) of this otremorine demonstrate higher affinities for
series of compounds correlated well with the peripheral muscarinic receptors than the cor-
k, and t,,, data. The slow cyclization rate of responding trimethylammonium and N-meth-
compound (3)and the extremely rapid cycliza- ylpyrrolidinium compounds (241).
tion rate of compound (6) were reflected in
weak or no CNS-related activities. As might be
predicted, compound (3) showed relatively
weak peripheral muscarinic activity (saliva-
tion) whereas compound (6)was potent. Com-
pounds (4) and (5)were cited as meriting fur-
ther study.
McN-A-343 (203) is a selective M, agonist (206a) X = CH2; Y = +S(CH&
and it has been reported to exhibit antinoci- (206b) X = CO; Y = +S(CH&
ceptive effects (238). It was suggested that (206c) X = CH2; Y = c+SC4H8
postsynaptic M, receptors are involved in an- (206d) X = CO; Y = c+SC4H8
tinociception, and that presynaptic M, recep-
tors may also be involved, on the basis that
they participate in modulation of acetylcho- However, the sulfur compounds have lower
line release. intrinsic activities than their nitrogen ana-
Of a series of congeners of compound (2031, logs. The sulfur compounds also demonstrate
(2)-204 and (2)-205 were concluded to be potent affinity for rat cerebrocortical tissue in
muscarinic partial agonists, showing five- and a (-)-[3H]-N-methylscopolaminedisplace-
16-fold higher potency, respectively, than that ment assay. Sulfonium congeners (207) bear-

ing chlorine or bromine at positions 3 or 4 of

the benzene ring retain selectivity for gangli-
onic muscarinic receptors, but they were con-
cluded to be partial agonists when compared
with the nitrogen system (203) (242). Nitro-
gen mustard congeners (208a and 208b) of
(203) demonstrate effects analogous to those
described previously for other oxotremorine-
based nitrogen mustards (243). (210) R = H; R' = morpholino
(211) R = NO2; R' = N(C2H5)2
4.6 Miscellaneous, Structurally Unique
Muscarinic Agonists
demonstrate analgesic activity. Shannon et al.
Several structurally unique muscarinic ago- (246), and references therein) presented a his-
nists have been identified. torical survey of muscarinic agonists that have
Compound (209) is claimed to be highly se- been reported to demonstrate antinociceptive
lective for the M, receptor (196); (210) and effects. These effects seem enigmatic, in that
(211) have been described as selective M, ago- the involvement of acetylcholine in excitation
nists devoid of classical muscarinic side effects of the pain sensation has been cited (247).
(196,244). Agonists at various G-protein-coupled musca-
Evidence was presented many years ago rinic receptors have potent analgesic activity,
(245) suggesting that some muscarinic agents but this is frequently accompanied by typical
muscarinic side effects (123). Analgesic prop-
erties of the arecoline congener (156) were
cited previously. Vedaclidine (212) appears to
be the most prominent of these agents, having
M, agonist and M,/M, antagonist activity
1,2,5-Thiadiazoleether analogs (213,214)
of vedaclidine (212) have also been viewed as
being analogs of the potent muscarinic agonist
aceclidine (149) (248).These ether analogs are
4 Cholinergics Not Closely Related Structurally to Acetylcholine

The R-enantiomer of (218) is highly selec-

tive for M, receptors over M, (252). The syn-
thetic route to (218) led to a 60:40 mixture of
Z:E oxime stereoisomers (253); this mixture,
on standing for 1 h at room temperature in

potent, efficaceous, and selective M, receptor

agonists. Replacement of the 3-oxyquinucli-
dine moiety of (213) or (214) by ethanolamine,
hydroxypyrrolidine, hydroxyazetidine,hydroxy-
isotropane, or hydroxyazanorbornane led to
compounds with high muscarinic receptor af-
finity adlor M, agonist efficacy. A concomitant
computational chemistry study led to the pro-
methanolic hydrogen chloride changed to an
posed description of an M, receptor pharma-
8515 equilibrium mixture of Z:E. Evaluation
cophore. No mention was made of testing of
of a series of azabicyclo[2.2. llheptane analogs.
this series of agents for antinociceptive effects.
of (218) revealed that with only a few excep-
Compound (215) inhibited jejunal contraction
tions, muscarinic activity resided in the
in the ferret, as well as demonstrating potent
Z-oximes, and that the E-isomers were inert
analgesic effects in the mouse writhing test
or very weakly active.
(249). An indole derivative, besipirdine (2191,dis-
plays some cholinomimetic effects, in addition
to prominent adrenergic actions. The mecha-
nism of the cholinergic effects was stated to be
unclear (254).

(215) 5 - R,6 - R,exo

A natural product, baogongteng-A (216)

was reported (250) to have agonist activity at
muscarinic receptors. A series of congeners
was prepared (2511, of which (2 17) was found
to be a potent muscarinic agonist with selec-
tivity toward M, receptors.


Conclusions about pharmacologically signifi-

cant conformations of cholinergic agonists
have been largely based on X-ray diffraction
studies and NMR (chiefly 'H) studies. Casy
(255) noted that in the cholinergic field, NMR
evidence complements the results of X-ray
studies. Casy (256) proposed four questions to
which conformational studies of cholinergic apart, and the 7, angle commonly has a value
agonists must be addressed: of 73-94", so that the N and 0 functions are
approximately synclinal (gauche). Many com-
1. Does the "active" conformation of a cholin- pounds with the 0-C-C-N+ moiety, where the
ergic ligand correspond to its preferred ste- oxygen-containing function is hydroxy or ac-
reochemistry or is an energetically less fa- yloxy, prefer the T, synclinal (gauche) N/O dis-
vored form bound to the receptor? position in the solid state: L-(+)-muscarineio-
2. Is there a unique mode of ligand binding to dide (31, the (4R)-(+)-cis-dioxolane(107),and
cholinergic receptors or do multiple modes the furan derivative (106). NMR data sug-
exist? gested (260) that acetyl-P-methylcholine (31)
exists in solution in a T, synclinal conforma-
3. May the dual effects (nicotinic and musca-
tion. However, there are many exceptions: in
rinic) of acetylcholine be explained in terms
the crystal state the potent muscarinic ago-
of conformational isomerism?
nists carbamoyl choline (number (19)in Table
4. Do agonist and antagonist ligands occupy 2.1) and (+)-trans-ACTM (221) (259) prefer
the same or different binding sites (with the T, anticlinal T, antiplanar conformations,
one or more features common to both)? as do the weakly active thio and seleno analogs
of acetylcholine (24) and (25).
These challenging questions remain, some
25 years later, largely unanswered, despite a
large body of chemical and biological work and
a voluminous literature. Indeed, establish-
ment of the existence of multiple subpopula-
tions of both nicotinic and muscarinic recep-
tors renders question 3 even more formidable.
The three-dimensional steric disposition of
the flexible acetylcholine molecule and those
of its congeners can be defined on the basis of L-(+)-Muscarone (102) exhibits a T, angle
torsion angle T. Summations and definitions of that is antiplanar (261).
nomenclature incident to use of torsion angles The crystal structures of certain nicotinic
are found in refs. 257 and 258. Structure (220) agents, for example, acetyl a-methylcholine
defines relevant torsion angles in the acetyl- (32) and lactoylcholine (17 in Table 2.1), have
choline molecule. torsion angle (7, and 7,) features similar to
The torsion angles T, and T, usually fall most muscarinic agents (262). In contrast,
close to 180"; the values of 7, and T, are more some cyclic analogs of aryl choline ethers ex-
useful in defining pharmacologically signifi- hibit maximum nicotinic effects when the T, is
cant conformations for acetylcholine and re- antiplanar ("transoid") (98).
lated molecules. From X-ray studies (259) it However, there is no assurance that any of
was concluded that in most cases T, values fall the preferred conformations determined ex-
in the range 180 2 36" (antiplanar), placing perimentally by X-ray or solution NMR meth-
the quaternary head and the acetyl group far ods, or by molecular orbital calculations (263),
5 Conformation-Activity Relationships of Some Cholinergic Agonists

represent the geometry of the agonist at cho-

linergic receptors; barriers to rotation in mol-
ecules such as acetylcholine are low (264,265),
and there is considerable rotational freedom
in the muscarine and muscarone systems
(256). It is well established as a broadly appli-
cable working hypothesis that an agonist mol-
ecule may interact with its receptor(s) in other
that its (the agonist's) lowest energy confor-
mation. The energy expended by the agonist's
assuming a higher energy conformation is
compensated for by the energy advantage of
the agonist-receptor interaction itself.
An alternate strategy is the study of confor-
mationally restrained acetylcholine analogs in
which the presumed pharmacologically signif-
icant portions of the molecule (the quaternary
ammonium head and the ester function) are in
relatively "frozen" positions, so that the
The trans-sulfur isostere (224)of the 3-ace-
three-dimensional geometry of the pharma-
toxypiperidinium system (222) is weak mus-
cophoric moieties is known. This approach
carinic agonist (6-10%as potent as acetylcho-
presents the disadvantage of frequently re-
line); the cis-isomer (225) is inert (270).
quiring molecules that are larger and more
complex than the parent, with altered recep-
tor affinity and different solvent partition
characteristics a possible consequence. Casy
(266) has discussed this difficulty in more de-
Schueler (267) suggested that the musca-
rinic and nicotinic effects of acetylcholine are
mediated by different conformers of the flexi-
ble molecule, and he evaluated structures (t)-
(222) ("transoid") and (223) ("cisoid") as ex-
amples of analogs of conformational extremes
of acetylcholine.
Both (222) and (223) exhibited only feeble
cholinergic effects, and the difference in activ-
ity between the two was not great. Both of the
enantiomers of (222)were far less potent than
acetylcholine at muscarinic sites (2681, but
they have intrinsic activities (compared with
acetylcholine) approaching unity. The S-enan- Both the cis and trans isomers (224 and
tiomer was somewhat more effective than the 225) display prominent nicotinic action; the
R-, demonstrating an S:R eudismic ratio of cis-isomer is approximately 20% as potent as
13.4. However, because of the ability of the acetylcholine and is approximately seven
piperidine ring to undergo ring inversion (con- times as potent as the trans-isomer. In the
formational flip) with concomitant change in trans-compound (224), the T, angle (S-C-C-0)
the T~ torsion angle, the piperidine ring of is described as anticlinal-antiplanar on the as-
compound (222) is not an ideal template for sumption that the chair conformer has an ax-
acetylcholine conformational investigation. ial S-methyl and an equatorial acetoxy (270).
Casy (269) has summarized literature confor- However, the ability of the thianium ring to
mational studies on compound (222). undergo ring inversion (175) presents the

same uncertainty of stereochemical interpre-

tation that was cited for the piperidinium ring
of compound (222).
The stereoisomeric tropyl acetates (226)
and (2271, in which a greater degree of molec-

A possibly serious defect in the design of

compounds such as the piperidinium (222),
the morpholinium (223), the tropines (226)
and (2271, and the decahydraquinoliniums
(228) is that these molecules do not bear the
trimethylammonium cation characteristic of
acetylcholine, but rather the quaternary head
is a part of a ring system. It was indicated
previously that incorporation of the nitrogen
atom of acetylcholine itself into a ring is detri-
mental to cholinergic activity and potency.
In a series of C-methylated trans-decalin
ular rigidity is imposed, are extremely weak congeners of (229), the 2,3-dimethyl com-
muscarinics, but both compounds exhibited pound (230) was the most potent muscarinic
potent nicotinic effects (271). in a guinea pig ileum assay [2% as active as
However, as demonstrated by Hardegger acetylcholine (274)l.
and Ott (272), some tropane ring systems can
assume a conformation in which the piperi-
dine ring is a boat. Therefore, the possibility of
ring inversion in (226) and (227) cannot be
precluded, and as with the piperidine and
thiane rings, conformational integrity is ques-
Stereoisomers of the trans-decahydro-
quinoline (228) (273) and the trans-decalin
(229) (88) displayed extremely low orders of
muscarinic effect, with the 2,3-trans-diaxial
isomer of (229) being the most potent of the
four stereoisomers of this structure (0.06%the
potency of acetylcholine). The most potent members of all of these
series of decalin-derived molecules have anti-
planar 7, stereochemistry. In the series of cy-
clohexane-derived compounds (231), the
(1R,2R)-trans compound was an extremely
weak muscarinic and the (t)-cis-isomer was
completely inert (275). Casy (256) suggested
that an energetically unfavored trans-diaxial
conformer (antiplanar 7,) for structure (231)
may be the pharmacologically active form of
the molecule. However, introduction of a t-bu-
tyl group into the cyclohexane system to sta-
5 Conformation-Activity Relationships of Some Choline!rgic Agonists


(231) All stereoisomers of (221) and (233) are
feeble nicotinics. X-ray analysis of (+)-trans-
bilize the 1,2-trans-diaxial geometry did not ACTM (221) (282) established the 7, angle as
lead to greatly increased muscarinic effect 137" (which is within the anticlinal range),
and because of the rigidity of the cyclopropane
The cis- and trans-cyclopentane systems ring, this value probably closely approaches
(232)have been described (256)as feeble spas- the solution conformation. The (IS, 2s) abso-
mogenics with a T~ angle near anticlinal. lute configuration of (+)-trans-ACTM super-
imposes on the equivalent centers in the po-
tent muscarinic agonists (S)-(+)-acetyl-p-
methylcholine (31) (see Table 2.2) and
(2S,4R,5S)-( + )-muscarine (3) (283). A race-
mic cyclobutane analog (234) of trans-ACTM
is much less potent than (2)-trans-ACTM
0-C-CH3 (284).

Congeners of acetyl y-homocholine (29)

and 4-acetoxybutyltrimethylammonium (30),
in which the amino alcohol entity is a part of
cyclopropane or cyclobutane ring systems, ex-
hibited feeble muscarinic and appreciable nic-
otinic effects (277, 278), but these results pro-
vide little insight into active conformations for No conformational study on structure
acetylcholine. The low cholinergic potencies (234) has been reported, and inspection of mo-
and activities of all of these preceding com- lecular models did not reveal any convincing
pounds probably preclude their being used as structural or steric differences between the cy-
abasis for acetylcholine conformation-activity clopropane and cyclobutane systems. The ra-
hypotheses, because "almost any compound cemic cis-cyclobutane isomer (235) is equipo-
with a quaternary nitrogen has some stimu- tent to the racemic trans-isomer (234) as a
lant or inhibitory activity at cholinergic recep- muscarinic receptor stimulant (285). Chothia
and Pauling (282) defined the following molec-
The cyclopropane ring has been exploited ular parameters for muscarinic agonism in
as the smallest system capable of conferring acetylcholine congeners (cf. structure (220),
conformational rigidity on an acetylcholine based on conformational analysis of (+)-trans-
analog (280, 281); (+I-trans-ACTM (221)
equals or surpasses acetylcholine's muscarinic
potency in two test systems, and it is an excel-
lent substrate for acetylcholinesterase. The
(-)-trans-enantiomer is several hundred
times less potent, and the racemic cis-com-
pound (233) is almost inert.

ACTM (221): r, = 180"; 7, = +73" to +1370; has increased greatly over the past several
r3 = 180 + 3 9 ; r4 = 180' or -1370. Inter- years, as a result of recognition of the poten-
atomic distances were defined as: N+-0' = tial value in therapy of Alzheimer's disease as
360; N+-C6= 450; Nt-C7 = 540 pm. Low po- well as of other defects in memory and learn-
tency or inactivity of certain acetylcholine de- ing. Giacobini (286) presented data confirm-
rivatives was attributed to deviation from one ing that a steady-state increase in acetylcho-
or more of these parameters. However, Casy line resulting from cholinesterase (sic)
(256) cited examples of deviations from these inhibition in the brain results in improvement
values in which high agonist activity is mani- of cognitive function and mild-to-moderate
fested. cases of Alzheimer's syndrome. Sussman and
It has not been possible to demonstrate un- coworkers (287) showed that the catalytic site
equivocally that acetylcholine assumes differ- of acetylcholinesterase is located at the bot-
ent conformations for interaction at nicotinic tom of a deep and narrow gorge surrounded by
and muscarinic receptors and/or at the sub- 14 aromatic amino acids. Moreover, these
populations of each major receptor subtype; workers presented evidence that the quater-
neither has this theory been disproved by the nary ammonium moiety of acetylcholine does
body of chemical and biological data. It must not interact with an anionic site on acetylcho-
be concluded that the relationship of acetyl- linesterase, but rather it binds with the ~ e l e c -
choline's molecular geometry to its physiolog- trons of Trp-84 (tryptophan). QSAR studies
ical roles is still not understood. (288) of a series of nicotine analogs and conge-
ners indicated that the cationic moieties of
various nicotinic receptor ligands interact
with aromatic groups on a,& and a, nicotinic
Symptoms resulting from an inadequate sup- receptors to an extent proportional to their
ply of acetylcholine may be relieved by block- receptor binding coefficients.
ing the body's acetylcholine-deactivating Figure 2.1 is a simplified representation of
mechanism. Interest in this category of agents the catalytic region of acetylcholinesterase

Figure 2.1.
6 Anticholinesterases

(289).Significant features are the Trp-84 aro- some or all of the methyl groups on the tetra-
matic center that anchors the quaternary methylammonium molecule tends to increase
head of the substrate; a serine residue, the potency (292). However, attempts to correlate
primary alcohol moiety of which participates biological test data with the calculated diame-
in a transesterification reaction with acetyl- ter of the unhydrated quaternary head led to
choline, resulting in acetylation of the en- inconclusive results.
zyme; and an imidazole ring (part of a histi- Belleau (293) calculated entropies and en-
dine residue) that, as a neighboring group, thalpies of binding to acetylcholinesterase for
participates in and facilitates the acetyl group a homologous series of alkyltrimethylammo-
transfer. The resulting acetylated serine moi- nium compounds RN+(CH,),, where R = CH,
ety is extremely labile and rapidly undergoes through n-C,,H,,. The observed relative po-
spontaneous hydrolytic cleavage to liberate tencies in the series were rationalized on the
acetate anion and to regenerate the active cat- basis of hydrophobic bonding phenomena cou-
alytic surface. pled with the ability of the alkyl chains to dis-
Taylor (290) described three classes of ace- place ordered water from the acetylcholines-
tylcholinesterase inhibitors, based on their terase surface.
mechanism of action: Edrophonium (236) combines a quater-
nary head for binding to the complimentary
1. Reversible inhibitors. site of the enzyme with a phenolic OH, which
2. Agents having a carbamate ester moiety presumably hydrogen bonds to a portion of the
that is hydrolyzed by acetylcholinesterase, esteratic area.
but much more slowly than acetylcholine.
3. Phosphoric acid- or phosphonic acid-de-
rived inhibitors, which are true hemisub-
strates for acetylcholinesterase.

Both the carbamates and the phosphorus

derivatives form a covalent (ester) bond with
the serine OH of the enzyme in essentially the
same manner as does acetylcholine. Taylor
(290)stated that the terms reversible and irre-
versible as they have been applied to the
carbamate and phosphorus-derived anticho- However, even this compound displays a
linesterase agents, respectively, reflect only rapidly reversible inhibition of the enzyme
quantitative differences in rates of cleavage of and its duration of action is short (290).
the esterified enzyme, and not an actual differ- Holmsted (294) tabulated an extended se-
ence in mechanism. ries of bis-quaternary ammonium compounds
that have been evaluated for anti-acetylcho-
6.1 Quaternary Ammonium Reversible linesterase activity; compound (237) is repre-
Inhibitors sentative of this category, which includes
some of the most effective enzyme inhibitors.
Simple quaternary compounds such as tetra-
methylammonium cation combine with the
substrate cation-binding site of the catalytic
surface of acetylcholinesterase and thus deny
acetylcholine's access to this site. These com-
pounds have a short duration of action due to
the facile reversibility of their binding and
rapid renal elimination (2901, and thus they
have minimal therapeutic utility. Cohen and
Oosterbaan (291) tabulated a comprehensive
list of tetraalkyl quaternary ammonium ace- Additional examples of anticholinesterase
tylcholinesterase inhibitors. Homologation of bis-quaternary ammonium compounds were

reported by Fulton and Mogey (295) and by tion. Compound (240) is a somewhat less po-
Cavallito and Sandy (296), who noted that tent acetylcholinesterase inhibitor in vitro
there is a gradual increase in antiacetylcho- than THA. However, the two compounds are
linesterase activity as the chain joining the approximately equipotent in reversal of sco-
two quaternary heads increases. The optimum polamine-induced memory impairment in
connecting chain length was stated to be five mice, a putative predictive model of activity in
or six carbons. In addition, enzyme inhibitory Alzheimer's disease. These data suggest that,
activity was maximal in those molecules in in addition to acetylcholinesterase inhibition,
which the substituent(s) on the quaternary ni- there may be other biochemical components to
trogen~were decidedly lipophilic. Later stud- the mechanism of action of (240). This specu-
ies (297) demonstrated efficient bonding of
decamethonium (238) to Torpedo acetylcho-
linesterase, contradicting earlier (296) reports.

6.2 Reversible, Noncovalent inhibitors

Related to 1,2,3,4-Tetrahydro- lation, which may be applicable to THA itself
9-Aminoacridine and to others of its active analogs and conge-
1,2,3,4Tetrahydro-9-aminoacridine (2391, THA, ners, is supported by a summation (303) of
tacrine) was described in 1961 (298) as a re- reported pharmacological effects of THA:
versible inhibitor of acetylcholinesterase and blockade of potassium channels; inhibition of
an even more potent inhibitor of butyrylcho- neuronal uptake processes; and inhibition of
linesterase. On the basis of X-ray crystal stud- monoamineoxidase. In the design of THA-like
ies it was reported (299) that a tryptophan res- anti-Alzheimer drugs, it has been emphasized
idue (Trp-84) at the catalytic surface of that selectivity of inhibition of acetylcholines-
acetylcholinesterase is the binding site for the terase as compared with inhibitory effect on
aromatic ring of (239). This is the same do- butyrylcholinesterase is a highly desirable
main that is believed to bind the quaternary strategy for minimizing unwanted side effects.
head of acetylcholine. A structure-activity study (304) addressed
modifications of the THA molecule, illustrated
in structure (241): X = H, 6-Cl, 7-C1,6-F,or 6-

Clinical efficacy in relief of the symptoms of

Alzheimer's disease was claimed (300) for
THA, but this positive finding is tempered by
its tendency to produce hepatotoxicity (301). CF,; R = H, alkyl, benzyl, ring-substituted
It was speculated (302) that the hepatotoxicity benzyl, or w-phenoxyalkyl.
of (239) might be related to its lipophilic char- Most of the compounds were inferior to
acter, and a (+)-1-hydroxy derivative (240) (239) as inhibitors of acetylcholinesterase, but
was designed in the hope that the OH group some were decidedly less toxic, and a few
would serve as a metabolic "handle" for glucu- were equieffective or superior to (239) in an
ronidation and subsequent facilitated elimina- assay evaluating their ability to reverse sco-
6 Anticholinesterases

polamine-induced memory impairment. Re- linesterase and is approximately 1000 times

canatini et al.(305)reported a comprehensive more potent than THA in inhibition of rat ace-
structure-activity study of THA derivatives tylcholinesterase. This preference of(245)for
substituted on positions 6 and 7 of the ring acetylcholinesterase and the fact that THA-
system and bearing selected groups on the like agents may exhibit unwanted side effects
9-amino group. QSAR studies and compara- arising from peripheral actions accompanying
tive molecular field analysis (CoMFA) of the desired central actions led to studies of a series
THA analogs permitted some conclusions to of heterodimeric analogs(246)of (245)(297).
be drawn with respect to the applicability of
these analytical techniques to formulation of
descriptive and predictive structure-activity
relationships of THA derivatives.
Addition of a fourth ring to the THA system
sometimes leads to compounds such as (2421,
which have marked selectivity for inhibition of
acetylcholinesterase over butyrylcholinester-

Compound (243) was reported to be 100-

400 times more potent than THA in inhibition
of neuronal uptake of serotonin. A series of

compounds related to (244) was designed by

"molecular duplication" of the THA molecule
(306).Some members of the series showed in-
hibitory action against acetylcholinesterase,
but they were less potent than THA. One com-
pound reversed cognitive deficits in middle
aged rats. Compound(245)was designed tak-
ing into account that there are two binding
sites for THA on acetylcholinesterase (307).
The compound is 10,000times more selective
for acetylcholinesterase than for butyrylcho-

Comparison of calculated desolvation free (310) to have memory enhancing effects in pa-
energies with IC,, values suggested the im- tients with Alzheimer's disease. However, for
portance of ligand hydrophobicity (low desol- clinical use it has a relatively short half- life,
vation free energy) for effective cation-n variable bioavailability, a low therapeutic in-
interaction of the homodimer (245) with pe- dex, and a multiplicity of unwanted cholin-
ripheral site(s). ergically related side effects.
(+)-Physostigmine, the enantiomer of the
6.3 Carbarnate-Derived Inhibitors naturally occurring alkaloid, has little effect
on acetylcholinesterase in vitro (311,312);it is
The prototype carbarnate-derived acetylcho-
linesterase inhibitor is physostigmine (247),
a weak centrally acting cholinergic agonist.
Eseroline (248), the ester cleavage product of
an alkaloid isolated from the seeds of the Cala-
bar bean, Physostigma venenosum. Physostig-
mine exhibits equal inhibitory activity against
acetylcholinesterase and butyrylcholinester-
ase (308).

physostigmine, is devoid of action toward

horse serum butyrylcholinesterase (313).
Rubreserine (249),an oxidation product of the

At the pH of the body fluids, a significant

proportion of physostigmine molecules is pro-
tonated at N1. This cationic species partici-
pates in binding of the molecule to the cata-
lytic domain of acetylcholinesterase, to permit
transfer of the N-methylcarbamyl moiety to
the OH of the serine residue, analogous to the
process described for the acetyl group of ace-
tylcholine. The resulting carbamylated en-
zyme is much more stable than the acetylated ester-cleaved physostigmine molecule, was re-
enzyme (t,,, for hydrolysis of the carbamy- ported to be approximately 11100 as potent as
lated enzyme is 15-30 min compared to <lms physostigmine as an inhibitor of horse serum
for the acetylated serine moiety) (290). Main- butyrylcholinesterase (314).
tenance of the enzyme in its carbamylated Eserine blue (250), formed from a reaction
form prevents its catalytic hydrolysis of ace- of rubreserine with ammonia (315), was re-
tylcholine for a prolonged time. In vivo, the ported to exhibit very low potency in a horse
duration of observable enzyme inhibition by serum butyrylcholinesterase assay (314). A
agents such as physostigmine is 3-4 h (290). later communication (316) suggests total inac-
Watts and Wilkinson (309)developed a kinetic tivity of these latter two physostigmine deriv-
scheme that was offered as a more adeauateA
explanation for carbamate-acetylcholinester- Brossi (317) prepared two short series of
ase reactions and provides an explanation for physostigmine homologs, one in which the
the observed catalysis of ester cleavage of car- substituent(s) on the nitrogen of the carba-
bamylated acetylcholinesterase by excess car- mate moiety was (were) varied, and one in
bamate. Physostigmine has been reported which the substituent on N1 was varied. Both
6 Anticholinesterases

C2H5,n-C3H7,or benzyl; and R" was a variety

of Cl-C, alkyl chains, phenyl, or benzyl. All
compounds were tested as their racemic mod-
ifications; selected ones were resolved, and
both enantiomers were studied. Two (-)-en-
antiomers, R = CH,, R' = C2H5, R" = n-
C7H15; and R = CH,, R' = C2H5, R" = n-
C,H,,, were more potent than physostigmine
or (251) in inhibition of acetylcholinesterase,
(+)- and (-)-enantiomers of the first series and they were six- to 10-fold more potent than
were prepared, but only the (-benantiomer of their respective (+)-enantiomers. These more
the second series was reported. Several of the active enantiomers had the same absolute con-
(-)-enantiomers (same absolute configura- figuration as physostigmine itself. Two bis-
tion as physostigmine) showed high potency in noreseroline derivatives (254a, 25413) showed
inhibition of acetylcholinesterase and of bu- marked antiacetylcholinesterase activity (316).
tyrylcholinesterase from a variety of sources.
Heptylphysostigmine (251) is a more li-
pophilic homolog and is reported (318) to be
less toxic than physostigmine, while retaining
its in vitro acetylcholinesterase inhibiting po-
Phenserine (2521, a selective inhibitor of
acetylcholinesterase with minimal effect on
butyrylcholinesterase, was cited as a possible
anti-Alzheimer drug (319).

Compound (254a) had relatively little ef-

fect on butyrylcholinesterase, whereas (254b)
was a potent inhibitor of both enzymes. The 3a
R enantiomers were less potent but they
showed the same selectivity as the 3a S com-
I pounds.
: It was postulated (320) that replacing the Studies aimed at incorporation of the car-
I N of the physostigmine molecule with a bamate ester moiety and the cationic site of
methylene group would increase the mole- physostigmine into simpler organic molecules
i ale's chemical and metabolic stability by con- have led to quaternary ammonium com-
; version of the potentially less stable aminal pounds based on structure (255).
i group to a more stable amino group. A series of The &substituted isomer of (255) is
&carbaphysostigmine congeners (253) was neostigmine. This compound is more stable
studied, in which R was H or CH,; R' was CH,, than physostigmine in aqueous solution, it

does not penetrate the blood-brain barrier,

deviate from the proposed 4.7 A requirement;
and also (unlike physostigmine) the pharma-
their N+-to-C=O distance is considerably
cological effects of neostigmine are pH inde-
greater (on the order of 8-8.5 A).
pendent (321). Neostigmine is extremely po-
Compound (258) was reported to be 190
tent, and it has replaced physostigmine as the
times more potent than physostigmine
reference drug for carbamamate-derived in-
against acetylcholinesterase, and it was 60
hibitors of acetylcholinesterase.
times more selective for inhibition of acetyl-
The position 3-substituted isomers of (255)
cholinesterase than for butyrylcholinesterase
and (256) frequently exhibit prominent miotic
activity (which was taken as a reflection of an-
Most anti-Alzheimer drug design studies
ticholinesterase activity), whereas ortho- and
directed at enzyme inhibition have sought
para-substituted molecules are inert (313).
compounds that inhibit acetylcholinesterase,
Foldes and coworkers (322)concluded that the
but have little or no effect on butyrylcholines-
optimum N+-to-C=O interatomic distance
terase. However, based on cited literature sug-
for compounds of the type (255) is 4.7 A. The
gestions that "inappropriate" butyrylcho-
meta isomers of these compounds meet this
linesterase activity increases the risk and/or
requirement, as does pyridostigmine (256),
progression of Alzheimer's disease, Brossi et
which is used clinically. Molecular models
al. (324) described physostigmine congeners
(eseroline and N, noreseroline carbamates)
having a high level of selectivity for butyryl-
cholinesterase rather than acetylcholinester-
ase. Possible therapeutic utility for these
agents was proposed, but no test data were

6.4 Phosphorus-Derived Inhibitors

Among the most powerful anticholinesterases
(inactivating both acetylcholinesterase and
demonstrate that the active m-quaternary plasma butyrylcholinesterase) are phospho-
ammonium phenylcarbamate systems can as- rus-containing compounds, most commonly
sume reasonable conformations in which their derivatives of orthophosphoric acid or of phos-
cationic heads and C=O groups coincide with phonic acids. The entire category is frequently
analogous groups in acetylcholine. Long (313) collectively called organophosphorus com-
described the ortho-substituted compound pounds although, strictly speaking, this no-
(257) as a potent acetylcholinesterase inhibi- menclature is inaccurate. Certain of these or-
tor, whereas the meta- andpara-isomers were ganophosphorus compounds are extremely
much less active. Compound (257) conforms toxic, and much of the developmental work in
to the 4.7-A N+-to-C=O distance require- the area was done with the object of preparing
ment, but its other two positional isomers do chemical warfare agents ("nerve gases").
not. It is noteworthy that physostigmine and Compounds in this category are potent and
its congeners (e.g., compounds 251 and 253 useful insecticides, and have been used world-
6 Anticholinesterases

wide for this purpose. The reaction between potency of the organophosphorus compounds
acetylcholinesterase and most organophos- parallels the ease of nucleophilic attack on the
phorus inhibitors has been presumed to occur phosphorus atom. Compounds in this category
only at the esteratic site of the enzyme, and include ester and amide derivatives of or-
the reaction here is a transesterification, com- thophosphoryl halides, pyrophosphate esters
parable to that involving the carbamate esters and amides, alkyl and aryl phosphonic acid de-
and acetylcholine itself. The reaction at the rivatives, and thiophosphoric acid derivatives.
esteratic site of acetylcholinesterase is en- Representative compounds are shown in Ta-
hanced by the geometry of the tetrahedral ble 2.5.
phosphates, which resemble the transition Holmsted (294, 325) and Hayes (326) have
state for acetate ester hydrolysis. The result- tabulated and discussed a large number of or-
ing serine-phosphorylated or -phosphonylated ganophosphorus acetylcholinesterase inhibi-
enzyme is extremely stable; if the R groups tors. Tabun, sarin, and soman (2, 3, and 4 in
(structure 259) are methyl or ethyl, regenera- Table 2.5) are among the most toxic "nerve
gases" known. OMPA (6) is inert as such, but
it is metabolized to an N-oxide derivative that
is the biologically active entity (327). Para:
thion (8)is inactive in inhibition of acetylcho-
linesterase in vitro; mixed-function oxidases
(in human liver) convert parathion into its ox-
I I ygen bioisostere paraoxon (9), the pharmaco-
serine residue
logically active metabolite (328). Echothio-
phate (7) is representative of inhibitors that
bind initially to the agonist cation binding site
tion of the enzyme by hydrolytic cleavage re- of acetvlcholinesterase
" as well as to the ester-
quires several hours. atic area. This compound is used clinically in
If the R groups are isopropyl, essentially no the treatment of certain types of glaucoma.
hydrolysis occurs and reestablishment of en- The 1,3,2-dioxaphosphorinane(260) is rep-
zyme activity can occur only after de novo resentative of organophosphorus acetylcho-
synthesis of the enzyme. A characteristic
structural feature of the anticholinesterase
phosphorus compounds is the grouping P-Z,
where Z is an electronegative moiety, a good
leaving group, and the cleavage of the P-Z
bond is accompanied by liberation of a large
amount of energy. The P-Z bond is eminently
susceptible to attack by nucleophiles, such as
the serine OH of the esteratic site of acetylcho-
linesterase. In general, the enzyme inhibitory
92 Cholinergics

Table 2.5 Some Phosphorus-Containing Acetylcholinesterase Inhibitors

Number Structure Chemical, Proprietary, or Generic Narne(s)
DFP, diisopropyl fluorophosphate, diisopropyl

Tabun, ethyl N-dimethyl


Sarin (GB),isopropyl

Soman, pinacolyl methylphosphonofluoridate

Tetraethyl pyrophosphate (TEPP)

6 Anticholinesterases 93

L Table 2.5 (Continued)

, Number Structure Chemical, Proprietary, or Generic Name(s)
(7) CzH6-0 Echothiophate,
i' \ f0
D diethoxyphosphorylthiocholine

S Parathion


linesterase inhibitors that were designed to

have a short duration of action (329). H , ~ ~ C H ~ - N ( C H ~ ) Z
This compound inactivates acetylcholines-
i terase by formation of "an unstable covalent
intermediate." The inhibited enzyme hydro-
lyzes spontaneously with t , , 10 min. Com-
pound (260) was proposed (329) to be a useful 0 0-
adjunct prophylactic agent against the insec-
ticide paraoxon and chemical warfare agents
such as soman.
A neurotoxic natural ~roduct.anatoxin-
a(s)(261),was isolated f r o i sever2 biological + 11
sources, including - a blue-green
- alga
- (330, (CH3)3N-CH2-CH2-O-C-S-R
Its high toxicity (LD,, = 20-40 pgkg in
mice) has been ascribed to anticholinesterase

6.5 Miscellaneous Inhibitors

These compounds are not hydrolyzed by
Thiocarbonate derivatives of choline (262a, acetylcholinesterase. Possible utility in treat-
262b) competitively inhibit acetylcholinester- ment of Alzheimer's syndrome was suggested.
ase from various sources (332). An a-chloro-P-phenethylamine (263) irreve

ibly inactivates acetylcholinesterase (333);the attachment of the ketonic carbon to position 8

active pharmacophoric species is the aziri- of the tetrahydrobenzazepine ring) demon-
dinium cation (264). strated potent in vitro inhibition of acetylcho-
The quaternary ion nature of the aziri- linesterase (337).It was active in a series of in
dinium cation allows for reversible complex vivo assays for CNS cholinergic effects, but it
formation with the cation binding site of the produced no significant peripheral cholinergic
enzyme, which precedes slow alkylation of the effects. Molecular modeling studies (docking
nucleophilic site (serine OH). Tetramethylam- analysis) of members of the series of com-
monium retards the irreversible inactivation pounds (266-268) indicated (338) that the N-
of the enzyme by this compound. benzyl group interacts with the same trypto-
Onchidal(265) is the principal constituent phan residue (Trp-84) as the aromatic ring of
of a secretion of glands of a mollusk (334). This THA (239). The other aromatic ring in these
inhibitors interacts with another tryptophan
residue (Trp-279) on the enzyme molecule,
and hydrogen bonding interaction between
the carbonyl group of the inhibitors
(266-268) and a tyrosine (Tyr-121) hydroxyl
on the enzyme seems to play an important
role. These data should be useful for the fu-
ture design of more potent, more specific,in-

compound is an irreversible inhibitor of ace-

tylcholinesterase. It is not a substrate for the
enzyme, and its mechanism of action appar-
ently does not involve acylation of the active
site serine hydroxyl. It was speculated (334)
that the a$-unsaturated aldehyde moiety
may be involved, through Michael addition, in
covalent bond formation with the enzyme.
Based on a molecular design strategy de-
rived from rationalizations concerning the to-
pography of the catalytic area of acetylcho-
linesterase, inhibitors based on compounds
(266) and (267) were identified (335, 336). Members of a series of 1-aroyl-3-[l-(benzyl-
Study of an extended series (structure 268 4-piperidiny1)ethyllthioureaderivatives (269)
and congeners of 266 and 267) revealed that are potent (submicromolar range) acetylcho-
one compound (268: R = H; Y = H; n = 3 and linesterase inhibitors (339).
6 Anticholinesterases 95

Comparable potency was retained by re-

placing the unsubstituted benzene ring with a
bioisosteric 2-pyridyl group. The guanidine
congener of (269) was almost inactive. In a
passive-avoidance test in rats, compound
(269) had maximal antiamnesiac activity at
0.03 mglkg with a therapeutic ratio greater
than 1000, and it displayed cholinergic side
effects only at high doses. Its potential use as
an antidementia agent was suggested (339).
The linear diamide (270) (caproctamine) was
described (340) as a more potent noncovalent
inhibitor of acetylcholinesterase than of bu-
It was reported to interact at both the ac-
tive site of the enzyme and at a second distal
site. It also showed prominent inhibitory ac-
tion at M, receptors, but it had only weak ef-
fect at M, and M, subtypes. In a search for less
flexible analogs of caproctamine (270),the tri-
cyclic system (271) was found to exhibit
"good" acetylcholinesterase inhibiting activ- (viewed as an analog of the physostigmine ring
ity (341). system), was almost as potent as physostig-
A carbamate derivative of the hexahydro- mine in vitro against human acetylcholinest-
chromenopyrrole moiety of (2711, ( +14272) erase and butyrylcholinesterase. Other ben-

zene ring position isomers of the carbamate value in treatment of Alzheimer's syndrome
moiety were much less potent. The two enan- was suggested. Donepezil(276) is a reversible,
tiomers of (272) exhibited approximately the noncompetitive inhibitor of acetylcholinester-
same potency as the racemic material. ase (344). Its affinity for this enzyme is ap-
Of an extensive series of l-benzyl-442- proximately 1250 times greater than that for
(N-benzoylarnino)ethyl]piperidine derivatives, butyrylcholinesterase. The compound pro-
designed and evaluated as inhibitors of acetyl- -
duced a marked increase in the acetylcholine
cholinesterase, the sulfone derivative (273) content of rat; cerebral cortex. Introduction of
was the most potent (342). a fluorine atom at the 2-position of the in-
This compound showed an 18,000-fold danone ring of (276) resulted in a compound
preference for acetylcholinesterase over bu- with increased potency (345). Additionally,
tyrylcholinesterase. It was a reversible inhibi- there was a significant difference in the anti-
tor in a concentration-dependent manner. cholinesterase activity between the enantio-
Benzisoxazole derivatives (274) and (275) mers of 2-fluoro-(276) compared to that of the
showed threefold inhibitory selectivity for ace- nonfluorinated molecule. Docking simulations
tylcholinesterase over butyrylcholinesterase of fluorodonepezil with acetylcholinesterase
(343). have been reported (346). A "hypothetical
Compound (274) produced dose-dependent binding site" for (276) a t the acetylcholines-
elevation of acetylcholine in mouse forebrain terase catalytic region was proposed (344). Of
after oral administration. Possible palliative a series of aminopyridazines, (277) was the
7 Acetylcholine-Release Modulators

most potent inhibitor of electric eel acetylcho-

linesterase (IC,, = 0.12 mM)(347). It showed
less activity against butyrylcholinesterase.
Huperzine-A (2781, an alkaloid from Hu-
perzia serrata Trev. (or Lycopodium serratum
Thunb.) is three times as potent as physostig-

R1 = n- and branched chain alkyl, phenyl
Rz, R3 = H, F, CH3

tion of binding free energies of tacrine-

huperzine-A hybrids. Overall, the results were
concluded to support the validity of the puta-
mine against acetylcholinesterase, but it is tive binding model described in ref. 349. Ex-
less potent against butyrylcholinesterase tension of the series of compounds (279) pro-
(348). duced halogenated and/or alkylated congeners
Several members of a series of hybrid mol- that were tight binding but reversible inhibi-
ecules of THA and huperzine-A (279) were tors of mouse brain acetylcholinesterase
more active against acetylcholinesterase than (351). These compounds showed ability to
cross the blood-brain barrier. Molecular mod-
(-)-huperzine-A, but they were not as selec-
eling simulations provided a basis to explain
tive for the enzyme (compared with butyryl-
the differences in inhibitory activity in this
cholinesterase) as huperzine-A (349). Molecu-
series of compounds.
lar modeling of compounds in the series with
acetylcholinesterase from Torpedo californica
showed them to interact "as truly THA-huper- 7 ACETYLCHOLINE-RELEASE
zine-A hybrids." However, it was noted that MODULATORS
acetylcholinesterase from Torpedo is some-
what different from that of humans. A subse- Structure-activity studies (352) of 3,3-disub-
quent paper (350) reported a study of predic- stituted oxindoles led to DuP-996 (linopir-

dine) (280); which enhances potassium- This newer compound is effective both in
evoked acetylcholine release in rat cortex, vivo and in vitro. Its mechanism of acetylcho-
hippocampus, and caudate nucleus, in vitro line release was not established, but it was
(353,354). suggested that the blockade of certain K'
This enhancement of acetylcholine release channels may be involved.
from nerve terminals occurs only when the Compound (282) stimulates the release of
release has been triggered (355). Compound acetylcholine (and also of dopamine and nor-
(280) is reported (355) to exert significant ef- epinephrine) in brain regions involved in
fects on the human central nervous system.
Dopamine and serotonin release are also en-
hanced by this agent, but release of glutamate,
GABA, and norepinephrine is unaffected. Fur-
ther structure-activity studies of 3,3-disubsti-
tuted oxindoles have been reported (3561, and
the potential utility of this category of com-
pounds in treatment of cognitive and neuro-
logical deficiencies was stressed. Compound
(281) was reported to be superior to (280) as
an acetylcholine-releasing agent (23).
memory and learning (37). This compound
was resolved, and it was reported that neither
the (R)nor the (5')enantiomer alone was as
active as the racemate in any of a series of
whole animal behavioral experiments.
One of the possible advantages to a thera-
peutic strategy for Alzheimer's disease or
other deficits in memory and learning using
acetylcholine-releasing agents is that such a
process would seem to permit stimulation of
both nicotinic and muscarinic receptors in the.
brain and to permit stimulation of all sub-
groups of acetylcholine receptors.

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and D. Liston, J. Med. Chem., 35, 1429-1434 339. J. L. Vidaluc, F. Calmel, D. Bigg, E. Carilla, A.
(1992). Stenger, P. Chopin, and M. Briley, Abstracts of
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Williams, Eds., Principles of Medicinal Chem- ican Chemical Society, Washington, DC,
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340. C. Melchiorre, V. Andrisano, M. L. Bolognesi, 348. A. P. Kozikowski,Y. Xia, E. R. Reddy, W. Tiick-

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Butler, D. S. Chapin, Y. L. Chen, J. L. Ives, Ganti, R. M. Scribner, V. J. Nickolson, S. W.
S. B. Jones, D. R. Liston, A. A. Nagel, D. M. Tam, and L. Cook, Abstracts of Papers, 196th
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42,730-741 (1999). ety, Washington, DC, 1992, MEDI 104.

Anticholinergic Drugs
School of Medicine
Vanderbilt University
Nashville, Tennessee

1 Introduction, 110
1.1Types and Selectivity of Antispasmodics, 111
1.2 Gastric Secretion, Peptic Ulcer, and
Anticholinergics as Antiulcer Agents, 111
1.3 Anticholinergics as Mydriatics
and Cycloplegics, 114
1.4 Anticholinergic Drugs in Prernedication
during Anesthesia, 115
1.5 Anticholinergic Activity as a Side Effect of
Drugs and Anticholinergic Syndrome, 115
1.6 Classification of Anticholinergic Agents
Based on Subtypes of Muscarinic Receptors,
2 Biocomparative Assay of Anticholinergics, 116
2.1 Antispasmodic Activity, 116
2.2 Antiulcer Activity, 118
2.3 Mydriatic and Cycloplegic Activities, 119
2.4 Miscellaneous Anticholinergic Activities, 120
3 Solanaceous Alkaloids, 120
3.1 History, 120
3.2 Chemical Structure, 120
3.3 Preparative Methods, 122
3.4 Molecular Factors in the Absorption, Fate,
and Excretion of Atropine and
Related Compounds, 122
3.5 Semisynthetic Derivatives
of Solanaceous Alkaloids, 124
4 Synthetic Anticholinergics, 126
4.1 Analogs of Atropine, 126
4.2 Receptor-Subtype-Selective Anticholinergics,
4.2.1 Tricyclic Benzodiazepines, 128
4.2.2 Benzothiazepines, 129
4.2.3 Quinuclidine-Based Antagonists, 129
4.2.4 Polymethylene Tetramines, 131
4.2.5 Indene Derivatives, 131
Burger's Medicinal Chemistry and Drug Discovery 4.2.6 Sila-difenidols, 132'
Sixth Edition, Volume 6: Nervous System Agents 4.2.7 Diphenylacetyloxy Derivatives, 132
Edited by Donald J. Abraham 4.2.8 Himbacine, 133
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 5 Structure-Activity Relationships, 133
Anticholinergic Drugs

5.1 Cationic Head, 133 6 Interaction of Anticholinergics at the Muscarinic

5.2 Cyclic Moieties, 141 Receptors, 151
5.3 Length of the Main Chain Connecting the 6.1 Kinetic Basis for the Mechanism of Action of
Cationic Head and the Cyclic Groups, 144 Anticholinergics, 152
5.4 Esteric Linkage, 146 6.2 Specificity of Antagonism, 152
5.5 Hydroxyl Group, 147 6.3 Molecular Basis for the Interaction of
5.6 Epoxy Group, 147 Acetylcholine and Anticholinergics at the
5.7 Stereoisomerism and Anticholinergic Muscarinic Receptors, 152
Activity, 147 7 Therapeutic Uses of Anticholinergics, 153
5.7.1 Opticalisomerism, 147 8 Molecular Basis for the Side Effects of
5.7.2 Derivatives of Tropine and Pseudo- Anticholinergics, 154
tropine, 149 9 Profile of Anticholinergic Activities of Various
5.7.3 Stereochemical Configuration, 150 Agents, 154
5.7.4 Dissociation Constants of Cholinergics 10 Nonanticholinergics as Antiulcer Agents, 155
and Anticholinergics, 150 11 Anticholinergics Developed for Specific Uses,
5.8 Compounds with Dual Action: Cholinergic 158
and Anticholinergic Activities, 150 12 Acknowledgments, 158

1 INTRODUCTION nerve transmission. These drugs do not pre-

vent acetylcholine from being released at
The role of acetylcholine as a parasympathetic nerve endings, although they may compete
neurotransmitter and its effects on smooth with the liberated neurohormone for cholin-
muscle and glands are reviewed elsewhere. ergic receptor sites. Acetylcholine is the chem-
Typical parasympathetic effects, in addition to ical transmitter at the postganglionic para-
cardiac inhibition and vasodilation in certain sympathetic nerve endings, as well as at
areas, are miosis and increased gastrointesti- autonomic ganglia and somatic neuromuscu-
nal motion and secretion. It is believed that lar junctions. Acetylcholine is also a chemical
acetylcholine is the common factor in many of transmitter at certain synapses in the central
these processes. Electrical stimulation of nervous system and drugs acting at central
parasympathetic nerves causes the appear- cholinergic sites are discussed elsewhere. Oif-
ance of acetylcholine at the neuromuscular ferent types of anticholinergic drugs antago-
junction; presumably, acetylcholine appears nize the actions of acetylcholine at the above-
regularly during the spontaneous functioning mentioned three types of peripheral synapses.
of the postganglionic fibers of the parasympa- Anticholinergic drugs that block somatic neu-
thetic nerves, and is regularly kept from accu- romuscular junction (curariform drugs) and
mulating by hydrolysis with acetylcholinester- autonomic ganglia (ganglionic blocking drugs)
ase. Spontaneous release of acetylcholine at are described elsewhere. The pharmacological
the parasympathetic nerve endings results in actions of anticholinergic drugs discussed in
the involuntary contraction or spasm of the this chapter mimic the effects of cutting the
muscle. Therefore, the contractions of the parasympathetic nerve supply to various or-
stomach, intestinal tract, heart, certain blood gans; therefore they are designated as para-
vessels, and many other structures in various sympatholytics. Muscarine mimics the actions
pathological situations are often attributed to of acetylcholine on the structures innervated
the amounts of acetylcholine in excess of nor- by parasympathetic nerves; it is relatively in-
mal requirements. Gastric secretion, saliva- active at autonomic ganglia and the somatic
tion, micturition, lacrimation, sweating, and neuromuscular junction. Parasympatholytics
miosis are influenced by acetylcholine. The that antagonize the actions of muscarine are
rates of these activities can be controlled by also known as antimuscarinic agents.
certain anticholinergic drugs. The classic parasympatholytic agent is at-
Anticholinergic drugs interfere with physi- ropine, and thus anticholinergic drugs used to
ological functions that depend on cholinergic be referred to as atropinic agents. Typical ef-
1 Introduction

fects produced by atropine are mydriasis, droxytryptamine spasm (lop7), histamine

tachycardia, decreased gastrointestinal peri- spasm and Ba2+ spasm Thus,
stalsis, and diminished secretions of gastric atropine is a highly specific anticholinergic
juice, saliva, and sweat. A large number of an- neurotropic spasmolytic.
ticholinergic agents have been synthesized The barium ion acts on all smooth muscles,
that have specific actions and uses. Although regardless of innervation, and is called a mus-
all anticholinergics could be considered as an- culotropic spasmogen. Drugs that relieve the
tispasmodics to different degrees, for conve- spasm produced by barium ions are called
nience they are divided into three categories: musculotropic spasmolytics. Papaverine and
(1)antispasmodics, which are specifically used nitrites are typical members of this class.
to relieve spasms of the bowel (e.g., irritable However, various drugs that resemble atro-
colon, spastic colitis); (2) antiulcer agents, pine manifest both kinds of spasmolytic action
which reduce gastric secretion; and (3) mydri- in widely varying situations.
atics and cycloplegics, which relax the sphinc- The ideal atropine-like antispasmodic
ter of the iris and the ciliary muscles. should be specific for the spasmogen, should
have selectivity for smooth muscles, and
1.1 Types and Selectivity of Antispasmodics
should abolish completely the spasm induced
Substances patterned on atropine are widely by the stimulation of the parasympathetic
used as antispasmodics of the gastrointestinal nerve to the organ. Further, the atropine-like
tract. Theoretically, any such substance that antagonist should be specific for the subtype of
relaxes the acetylcholine-induced spasm of the muscarinic receptor localized in the organ.
smooth muscles in suitable doses can be None of the available antispasmodics satisfies
termed an antispasmodic. In practice, not ev- all these requirements. However, a great
ery anticholinergic agent can be used as an many compounds have been synthesized with
antispasmodic. The reason is that in addition the hope of developing drugs that will exhibit
to their spasmolytic action, anticholinergics more selective antispasmodic action and have
influence the functions of other organs includ- fewer side effects than those of atropine.
ing heart, sweat and salivary glands, and iritic Some of these antispasmodics show rela-
and ciliary muscles, producing side effects. tive selectivity toward the subtype of musca-
Moreover, a number of them in small doses rinic receptor localized in smooth muscle cells.
cause undesirable disorders in the central ner-
1.2 Gastric Secretion, Peptic Ulcer, and
vous system (CNS). The same antispasmodic
Anticholinergics as Antiulcer Agents
is not suitable for the spastic states of all or-
gans. Further, there are differences in the in The pathophysiologyof peptic ulcer is not fully
vitro and in uivo efficacies of antispasmodics. known and, in the present state of knowledge,
Atropine abolishes the acetycholine-induced it is not possible to present the pertinent nor-
spasm of guinea pig ileum completely; how- mal physiology briefly. For a detailed discus-
ever, it is a familiar clinical experience that sion on the physiology and chemistry of gastric
atropine does not antagonize completely the secretion and the pathologic physiology of pep-
spasm caused by increased tone of the intesti- tic ulcer, reference should be made to reviews
nal vagus nerve. on the subject (1-5). The following is a brief
A number of agents cause spasm of the gas- summary of the gastric secretion and its rela-
trointestinal tract. The spasm may be induced tionship to peptic ulcer, a knowledge of which
not only by acetylcholine but also by hista- is necessary to understand the problems of de-
mine, 5-hydroxytryptamine, or barium chlo- veloping antiulcer agents.
ride. Atropine and other anticholinergics are Gastric juice contains a mixture of water,
effective mostly against acetylcholine-induced inorganic ions, hydrochloric acid, pepsino-
spasm, and less against the remaining three gens, mucus, various polypeptides, and the in-
spasmogens. Against a spasm induced by ace- trinsic factor. Pepsinogens are precursors of
tylcholine, atropine is effective at the lowest the proteolytic enzymes, pepsins. They are
concentrations (e.g., lop9 g/mL). Higher con- readily converted into the corresponding pep-
centrations are necessary to antagonize 5-hy- sins by either acid or pepsin itself. Conversion
Anticholinergic Drugs

by acid is instantaneous at pH 2.0. In humans, vous component, the intestinal phase includes
gastric juice contains hydrocholoric acid dur- humoral stimulation of secretion by unknown
ing the period of interdigestive secretion as agents. Gastrin released from the small intes-
well as during the period of digestive secre- tine may be involved. The response to what-
tion. Although the mechanisms of interdiges- ever humoral agent comes from the intestine
tive secretion are not known, they depend is greatly increased when subthreshold doses
partly on the tonic activity of the vagus. The of cholinergic drugs are given.
gastric secretory activity during the period of A number of humoral inhibitors of gastric
digestive secretion may be divided into three secretion arise in the small intestine. They are
phases, cephalic, gastric, and intestinal. Each termed enterogastrones. An enterogastrone is
phase is named to denote the region in which present in the jejunum and duodenal mucosa.
the stimuli act to induce gastric secretion. It is released in the presence of fat and inhibits
In the cephalic phase the stimuli are initi- gastric secretion and motility. The hormone
ated in the central nervous system. The stim- secretin, which stimulates pancreatic secre-
uli are the sight, smell, taste, and thought of tion, is an enterogastrone. It is produced in the
food, which act through conditioned and un- proximal duodenum and inhibits gastric se-
conditioned reflexes. The final efferent path is cretion in the presence of acids. Cholecystoki-
the vagus nerve. The impulses in the vagus nin, which is the same as pancreozymin, and
nerve stimulate the secretory cells in the gas- gastrin share the same terminal tetrapeptide.
tric glands. Acetylcholine, which is released Given alone, cholecystokinin is only a mild
from the postganglionic nerve endings, exerts stimulant of gastric acid secretion. It is a com-
a direct action on the secretory cells. Adminis- petitive inhibitor of the receptor for gastrin,
tration of atropine abolishes this phase. The which is a powerful stimulant of gastric acid
secretion is high in acid and pepsinogens, and secretion. Therefore, in the presence of gas-
its concentration of mucus is lower than that trin, cholecystokinin decreases the total out-
of the basal secretion; mucus output rises put of acid. Glucagon (and possibly enteroglu-
8-10 times as the volume increases. cagon) reduces the gastrin-induced acid
The gastric phase of secretion begins copi- secretion by noncompetitive inhibition of the
ously as soon as the food enters the stomach, receptors to gastrin. A gastric inhibitory
and it may continue 3-4 h, with a total volume polypeptide (GIP) that is present in duodenal
of 600 mL or more of strongly acid juice con- mucosa inhibits both histamine- and gastrin-
tain ng a high concentration of pepsinogens. induced acid secretion. A vasoactive intestinal
The gastric phase of secretion is caused by lo- peptide (VIP), which has been isolated from
cal and vagal responses to distension and by small intestinal mucosa, inhibits histamine-
the hormone gastrin, released by the musosa induced acid secretion. GIP and VIP are two
of the pyloric gland area. The local nerves of possible enterogastrones whose significance
the pyloric area are confined to the mucosa has yet to be established.
and are cholinergic. Irrigation of the pyloric Histamine, the exact role of which is not
gland area with acetylcholine releases gastrin, clearly understood, stimulates secretion of
and this liberation of gastrin is abolished by gastric juice that is rich in hydrochloric acid.
atropinization. There is a synergism between Recently, histamine receptors have been di-
gastrin and acetylcholine at the target cells; vided into three types, HI, H2, and H3. Stim-
the effect of injected gastrin on both acid and ulation of H2 receptors by histamine results in
pepsinogen secretion is increased two- to increased gastric acid secretion. H2 receptor
eightfold by subthreshold parasympathomec- antagonists (burinamide, metiamide, cimeti-
tic stimuli, and it is strongly inhibited by atro- dine) inhibit histamine-induced gastric acid
pinization. secretion in both humans and animals. In
The intestinal phase that begins when humans, H2 antagonists inhibit not only his-
chyme passes from the stomach to intestine, tamine- but also pentagastrin (a synthetic an-
contributes about 10% of the total response to alog of gastrin)-stimulated gastric acid secre-
a test meal. Protein and its digestion products, tion. This suggests that, at least in humans,
milk, dilute alcohol, and acid itself are effec- gastrin acts partially by histamine. Blockage
tive stimulants. Although there may be a ner- of acetylcholine receptors by atropine and his-
1 Introduction

Anticholinergics HPreceptor
(ACh) antagonists (H)
-Vagus nv
er, CP I Histamine

Antrum - Gastrin -
(-) Local hormones:
prostaglandins (G, H)

.- ,
Gastrin - (+) Parietal cell
- Mucus secretants

Enterogastrones 4 \ I

Secretin (G) I
~ntero~luca~on (G)
Cholicystokinin (G)
GIP (G, H)
Fat (G, H)
Pepsinogen - Pepsin Pepsin inhibitors
(sulfated polysaccharides)
Figure 3.1. Interactions among neuronal and hormonal factors and pharmacological agents during
cephalic (Cp),gastric (Gp),and intestinal (Ip) phases of gastric acid secretion by parietal cell. ACh,
acetylcholine; GIP, gastric inhibitory peptide; VIP, vasoactive intestinal peptide; MI, muscarinic
receptor; HZ,histamine HZ receptor; GR, gastrin receptor; (+), stimulation of acid secretion; (-), ,

inhibition of acid secretion. In parentheses, next to the inhibitory agents, is indicated the blocked
stimulant agent (ACh, acetylcholine; H, histamine; G, gastrin).

tarnine receptors by H2 antagonists results in The interplay among various neuronal

reduction of the effectiveness of gastrin to in- and hormonal factors in the gastric acid se-
duce acid secretion. cretion by the parietal cell during cephalic,
Therefore, there seems to be a complex in- gastric, and intestinal phases are schemati-
teraction among the three receptors, acetyl- cally shown in Fig. 3.1. In addition to being
choline receptors, H2 receptors, and gastrin inhibited by atropine-like agents and entero-
receptors involved in the acid secretion by pa- gastrones shown in Fig. 3.1, the acid secretion
rietal cells. is inhibited by gastrone in the mucus of hu-
Among local hormones and messengers, man stomach, by urogastrone isolated from
prostaglandins (PGE,, PGA,) adenosine 3',5'- the urine of men and dogs, by strongly acid
monophosphate (cyclic AMP, CAMP) inhibit solutions in the duodenum, and by stimula-
both pentagastrin- and histamine-stimulated tion of the &mpathetic nervous system.
gastric secretion. According to present evi- Peptic ulcer occurs in the pyloric region of
dence, all hormones that reduce gastric acid the stomach or the first few centimeters of the
secretion increase both adenylcyclase and in- intestine. The gastroduodenal muscosa is ex-
tracellular CAMP activity. Conversely, all hor- posed constantly to mechanical, physical, and
mones that primarily stimulate gastric acid se- chemical insults, some of which have already
cretion reduce intracellular CAMP levels. been described. A peptic ulcer does not develop
Therefore, CAMPis involved in the final links without the presence of a pepsin-containing
of gastric acid secretion. juice of such low pH that it can exert a peptic
Anticholinergic Drugs

influence on the gastric wall itself. The extent completely for many hours (6). Its effect on
of this insult is determined by the number of secretion during the feeding of milk and cream
acid- and pepsinogen-producingcells, their ir- is significant (7, 8). However, anticholinergic
ritability, and/or the magnitude of the stimuli drugs do not effectively perform a "medical
that reach them. These stimuli are partly ner- vagotomy" and they do not effectively reduce
vous (vagal) and partly hormonal (gastrin, gastric acidity to the extent of achlorhydria
corticosteroids). when patients are fed (8, 9). The effective an-
The healthy stomach does not digest itself. ticholinergic agent as an antiulcer drug should
Counteracting the aggression are defensive be selective for the subtype of muscarinic re-
factors such as buffering and dilution by food, ceptors localized on the secretory cells of gas-
inhibition of the secretion of gastric juice, and tric glands as well as mucosa of the pyloric
drainage of gastric contents. In addition, how- gland area. Anticholinergics selective for mus-
ever, the local condition of the mucosa (the carinic receptors of M1 subtype are useful in
mucosal resistance) is also of importance. decreasing gastric acid secretion.
Some of the determinants of mucosal resis-
tance are the mucous barrier, the local circu-
1.3 Anticholinergics as Mydriatics
lation, and the healing capacity of the mucosa.
and Cycloplegics
A peptic ulcer forms when the insult is more
powerful than the defense. In the case of duo- The size of the pupil is determined by the bal-
denal ulcers, the powerful irritation is often ance of forces exerted by the dilator muscles
the important factor; in gastric ulcers it is the fibers (sympathetically innervated and radi-
insufficient defense. ally arranged) and the constrictor muscle fi-
The ideal agent for the treatment of the bers (parasympathetically innervated and cir-
peptic ulcer would be one that selectively inac- cularly arranged) of the iris. Normally both
tivates pepsin or inhibits the output of hydro- sets of muscle fibers have a constant degree of
chloric acid so as to maintain the pH of the tonus and act reciprocally to dilate or constrict
gastric contents at about 4.5 for long periods the pupil. Any substance that paralyzes the
after its oral ingestion. It should produce no, constrictor muscle fibers (parasympatholytic)
or only minimal, side effects, induce no toler- allows the unopposed tone of dilator muscle
ance, and be inexpensive. It should be effective fibers to widen the pupil.
during all periods and phases of gastric secre- Acetylcholine is the transmitter between
tion and prevent the formation of ulcers. the constrictor muscle fibers and the parasym-
Atropine-like anticholinergics do not sat- pathetic nerve that innervates them. There-
isfy all requirements of an antiulcer agent. fore, acetylcholine and its congeners stimulate
They block acetylcholine action at the neu- the constrictor muscle fibers of the iris and
roeffector junction of the vagus. They give re- constrict the pupil. Atropine and related com-
lief to patients with a peptic ulcer by their an- pounds paralyze the constrictor muscle fibers
tisecretory and antispasmodic effects. They and cause widening or dilatation of the pupil.
decrease the basal hydrochloric acid and pep- The ciliary muscle is innervated by the
sin secretion, thereby allowing the healing of parasympathetic nerve, and acts to decrease
ulcers. The antispasmodic effects of atropine- the tone on the supporting muscle fibers of the
like agents are as consistent as their antisecre- lens, and thus increases the accommodative
tory effects. Motor activity is closely related to power of the eye. Acetylcholine and its conge-
ulcer pain, and the pain-relieving action of an- ners constrict the ciliary muscle fibers, and
ticholinergic agents seems to be related to atropine and related compounds paralyze the
their effect on depressing motor activity (anti- ciliary muscle.
spasmodic effect). Mydriatics are drugs that dilate the pupil,
An "effective" atropine-like anticholinergic but have minimal effect on the ciliary muscle
drug is capable of favorably influencing the and thus on accommodation. Cycloplegics are
excessive gastric secretion under certain con- drugs that partially or completely paralyze ac-
ditions. It exerts a significant effect on acid commodation. Most of the anticholinergics
secretion during the basal and interdigestive have both properties to varying degrees. For
night secretion to the point of abolishing it mydriatics other than anticholinergics and for
1 introduction 115

drugs that constrict the pupil (miotics), the properties that disturb patient recovery be-
appropriate chapter should be consulted. cause of their anticholinergic effects on the
Mydriatics and cycloplegics are special CNS (11).These effects are termed central an-
types of antispasmodics. In clinical practice ticholinergic syndrome (CAS) and are dis-
mydriasis is produced by local instillation of cussed in different chapters on centrally act-
the chosen drug into the conjunctival sac. This ing drugs (volume 4). These effects can be
enables one to produce the desired effects on reversed with physostigrnine, the centrally ac-
the eye with minimal systemic effects. How- tive cholinesterase inhibitor, which has a spar-
ever, such compounds should possess proper- ing effect on acetylcholine molecules at mus-
ties that allow them to penetrate the cornea in carinic receptor sites. An increased number of
effective concentrations. There are no signifi- acetylcholine molecules displace the mole-
cant differences between the muscarinic re- cules of anticholinergic drug from the musca-
ceptors of the guinea pig ileum or the rabbit rinic receptor sites.
iris, as judged by the binding characteristics of
potent anticholinergic agents. Muscarinic re- 1.6 Classification of Anticholinergic Agents
ceptors in both tissues are possibly of the M3 Based on Subtypes of Muscarinic Receptors
subtype. If anticholinergic drugs are available Acetylcholine produces its parasyrnpathomi-
that are selective for muscarinic receptors on metic effects by binding at cholinergic recep-
constrictor muscles and ciliary muscles, myd- tors of the muscarinic type. The classical anti-
riatic and cycloplegic effects can be produced cholinergic agent, atropine, binds to the same
by different drugs. muscarinic receptors and prevents acetylcho-
line from binding to these receptors and elic-
1.4 Anticholinergic Drugs in premedication iting muscarinic responses. Based on modern
during Anesthesia developments in the design of relatively sensi-
Prevention of some undesirable side effects tive antagonists for muscarinic receptors in
during anesthesia has been considered a func- different tissues (12-15), muscarinic receptors
tion of premedication with anticholinergic have been subdivided into three (possibly five)
drugs. For example, atropine is a popular an- subtypes M1 to M5 (Table 3.1). All muscarinic
ticholinergic agent that has been used for its receptors are glycoproteins of molecular
antisialogogic, antibradicardia, and anti- weight of 80,000 and have seven membrane-
emetic effects (10). The emphasis of using an- spanning regions. All of the receptors have a
ticholinergic drugs during premedication has slow response time (100-250 ms) and are cou-
been changing over the years because of the pled to G-proteins (13, 14). They act directly
availability of inhalational anesthetic agents on ion channels or are linked to second-mes-
that are better than ether. An anticholinergic senger systems, attenuation CAMPformation
agent (e.g., atropine), although no longer re- (16, 17), and formation of inositol triphos-
garded as an essential premedicant under all phate and diglyceride (16, 18). The final effect
circumstances, does have specific applications of activation of these receptors can be to open
for injured patients and children. Atropine or close K' channels, Ca2+ channels, or C1-
(0.6 mg, i.v.1 blocks the muscarinic actions of channels. These multiple channel activities
suxamethonium (succinylcholine), bradycar- lead to either depolarization or hyperpolariza-
dia, and salivation during crash induction of tion of the cell membrane. The final responses
anesthesia in an injured patient (10). Admin- are either excitatory or inhibitory. Atropine
istration of an anticholinergic drug to prevent blocks all of these activities and does not dis-
bradycardia in children in response to suxam- tinguish subtypes. Selective muscarinic ago-
ethonium or tracheal intubation is desirable. nists and antagonists that will distinguish dif-
ferent subtvpes are needed. Further, it will be
" a

a major advance to obtain information to indi-

i 1.5 Anticholinergic Activity as a Side Effect
cate that each subtype performs a specific
f of Drugs and Anticholinergic Syndrome
function. Then it will be possible to develop
1 Many of the drugs used in current medical
practice, especially anesthetic drugs and other
specific anticholinergic drugs that are useful
only as (1)antispasmodic, (2)antisecretory, or
drugs used as adjuvants to anesthesia have (3) mydriatic agents. With certain anticholin-
11 6 Anticholinergic Drugs

Table 3.1 Provisional Division of Muscarinic Receptors (M), Their Agonists

and Antagonists into Five Subtypesa
M Subtype M1 M2 M3 M4 M5
Previous names M2, Mw
Cardiac M, Glandular M2
Tissue locationb Lower esophageal Heart Glands,
sphincter, smooth
gastric glands, muscle,
CNS ganglia CNS
Selective McN-A-343 - -
Selective Pirenzepine Methoctramine HHSID - -
antagonistsd (+)-Telenzepine AF-DX 116 p-F-HHSID Himbacine
Himbacine (High Affinity)
pathway' Kf channel
Gene m2 m3
Amino acids 466 590
"Summarized from Refs. 12-18.
bCNS,central nervous system sites.
'Selective agonists for receptors M2-M5 are not available.
dHHSID, hexahydrosiladifenidol; p-F-HHSID: p-fluoro-hexahydrosiladifenidol.

ergic agents, some degree of selectivity (not 2.1 Antispasmodic Activity

specificity) has been attained to produce anti-
In studying drugs more or less like atropine, it
spasmodic, antisecretory, or mydriatic effects
is customary to test their antispasmodic ac-
(Table 3.2). No antagonist has a potency on
tion on smooth muscles, such as the isolated
one receptor subtype that is more than 10
guinea pig ileum, duodenum, or jejenum of
times higher than its potency on other sub-
rabbit, or rat intestine. Acetylcholine or any
types. All receptor subtypes have K, values for
one of the cholinergics may be used as a spas-
(-)-N-methylscopolamine (NMS) and (-1-3-
mogen, and the ability of the antispasmodic to
quinuclidinyl benzilate (QNB) of less than 1.0
inhibit or abolish the cholinergic-induced
nM (13). NMS and QNB are standard anticho-
spasm may be measured. Helical strips of
linergic agents in addition to atropine to com-
blood vessels with intact endothelium (e.g.,
pare anticholinergic potencies at muscarinic
strips of rat aorta) can also be used to evaluate
the antispasmodic activity of anticholinergic
drugs (21). The antagonistic activities may be
2 BIOCOMPARATIVE ASSAY expressed as affinity constants or relative mo-
OF ANTICHOLINERCICS lar activities in relation to a standard antago-
nist. The selectivity of the antispasmodic ac-
Many of the methods of obtaining experimen- tivity may be determined by using different
tal evidence for the antispasmodic, antiulcer, spasmogens (e.g., histamine, 5-hydroxytryp-
and mydriatic activities do not measure pre- tamine, nicotine, and barium chloride).
cisely and selectively only one type of pharma- Thiry-Vella fistulas (19), prepared at vari-
cological activity. However, the techniques ous levels of the gastrointestinal tract, have
that are available (19,20), if used with an un- been used in the conscious dog for determin-
derstanding of their scope and limitations, can ing motility by (1)placing an indigestible bo-
provide useful information in the develop- lus in the oral end of the fistula and determin-
ment of anticholinergic agents and their struc- ing the traverse time before and after
ture-activity relationships. treatment with drugs; (2) placing a balloon
Table 3.2 Derivatives of Solanaceous Alkaloids and Their Semisynthetic
- Substitutes"
- . if any, of Molecular
Generic Name Trade Names Dose or Preparation ~odifi&ion Therapeutic Use
Atropine sulfate USP 0.5 mg (oral i.v or s.c.); Mydriatic with long recovery period;
0.5-1.0% ophthalmic preanesthetic medication to decrease
solution secretions, treatment of Parkinsonism,
and anti-ChE poisoning
Atropine tannate Atratran 1-2 mg (tablet) Slow absorption with sustained Antispasmodic in ureteral and renal colic
release of the alkaloid
Ipratropiumb bromide Atrovent Inhaler Low systemic absorption Bronchodilator in asthma
Atropine N-oxide X-tro 0.5-1.0 mg (capsule) Slow release of the alkaloid Same as atropine for oral use
hydrochloride Genatropine
Hyoscyamine hydrobromide 0.25-1.0 mg Possibly fewer central effects Same as atropine for oral use
than atro~ine because of
small doses administered
Methylatropine bromide Mydriasine 0.52% solution Mydriatic with short recovery Mydriatic
d Methylatropine nitrate Metropine 1-5% solution Same as above Mydriatic
v Scopolamine hydrobromide 0.6 mg (oral, (s.c.1; Central depressant ("twilight As a sedative during pre- or
USP 0.2% solution sleep") postoperative gynecologic care
Genescopolamine 1-2 mg Gradual release of alkaloid Same as above
Methscopolamine bromide Pamine 2.55.0 mg (oral); 0.25- Parasppatholytic without Antisecretory and antispasmodic in
NF Lescopine 1.0 mg (s.c. or i.m.1 central effects peptic ulcer
Methscopolamine nitrate Skopolate 2-4 mg (oral) Same as above Same as above
NND Skopyl 0.25-0.5 mg (s.c. or
Homatropine hydrobromide 1-2% solution Mydriatic with recovery period Mydriatic
USP less than that of atropine
(see Table 3.18)
Homatropine methyl Novatropine 5 mg (oral) Parasppatholytic without Antisecretory and antispasmodic
bromide NF Mesopin central effects
Anisotropine Valpin 10 mg (oral) Parasppatholytic without Antisecretory and antispasmodic
methylbromidec Endo central effects
"For details of the preparations and their uses, standard references (97-99) in pharmacology should be consulted.
"8-Methy1-3-(2-propy1pentonoy1oxy) tropinium bromide odatropine bromide.
Anticholinergic Drugs

containing water and attached to a kymo- ligation and the stomach contents are col-
graphic recording system in the fistula and re- lected for examination. The stomach is opened
cording the pressure waves and their alter- along the greater curvature and the ulcers are
ations by the action of drugs; or (3) placing a examined and scored by a suitable scheme
French catheter in the aboral end of the fis- such as 0 = normal, 1 = scattered hemorrhagic
tula, connecting it to a suitable recording sys- spots, 2 = deeper hemorrhagic spots and some
tem, and thus making a record of normal pres- ulcers, 3 = hemorrhagic spots and ulcers, and 4
sures and those occurring after treatment. = perforation. Variable results have been re-
Other qualitative and quantitative meth- ported by investigators using this technique.
ods to study the antispasmodics have been de- Production of chronic experimental peptic
scribed (19). These include (1)the fluroscopic ulcers in dogs (or rats) by the Mann-William-
study of the gastrointestinal motility and (2) son procedure (36) is one of the standard
the use of an ingestible pressure-sensitive ra- methods. The gastric juice is diverted into the
dio-telemetering capsule (Transensor) for intestine some distance from the pancreatic
measuring the pressure in the gastrointesti- and biliary secretions. The objective is
nal tract. achieved by isolating the duodenum from the
The subtype of muscarinic receptor in the pylorus and the jejunum. The oral end of the
smooth muscle has been characterized as M3 duodenum is closed and its distal end is anas-
by use of selective anticholinergics and differ- tomosed with a loop of ileum, so as to dis-
ent smooth muscle preparations from differ- charge the pancreatic and biliary secretions
ent species. These smooth muscle tissues in- into the lower portion of the bowel. The cut
clude (1)trachea (22), ileum (23, 241, uterine end of the jejunum is then anastomosed to the
artery (25), and submucosal arterioles of pylorus. About 95% of dogs so prepared de-
guinea pig (26); (2) aorta (27) and coronary velop typical chronic peptic ulcers just distal to
artery of rabbit (28); and (3) trachea (291, the gastric anastomosis with the jejunum.
aorta (30), and iris (31) of rat. Human uterine With similar operative procedures 85% of rats
arteries (32),airways (331, and ciliary muscles develop gastric, marginal, or jejunal ulcers.
(34) have also been shown to contain the M3 The complete reversal of the duodenum in
type of muscarinic receptors. dogs produces chronic peptic ulcers in about 6
months (19). These animals maintain their
2.2 Antiulcer Activity
weight until the development of ulcerations
The problems encountered in testing drugs for and might become a useful preparation for de-
antiulcer activity result in part from a lack of tecting and comparing antiulcer activity.
complete understanding of the physiological Stress produces ulcers in the rats, which
and biochemical mechanisms involved in the could be used to test the antiulcer activity of
formation of ulcers, and in part from the test- drugs (37). Rats fasted for 48 h and immobilized
ing of drugs for activity on normal or quasi- in a galvanized screen cage under light ether
normal animal preparations, although they anesthesia develop ulcers in the glandular re-
are ultimately applied to abnormal or patho- gion of the stomach after 4 h of restraint. The
logical human states. The various methods estimate of severity can be all or none, or may be
differ in producing ulcers in experimental an- coded in the same way as the Shay preparation.
imals (19). One of the side effects of adrenocortico-
A preparation developed by Shay et al. (35) tropic hormone (ACTH)and corticoid therapy
has been used to test for antiulcer activity on in humans is the development or reactivation
an all-or-none basis. The ligation of the pylo- of gastroduodenal ulcers. Daily subcutaneous
rus of rats, previously fasted for 48-72 h, leads administration of cortisol or A'-cortisol to rats
to the accumulation of acid gastric contents for 4 days results in the regular development
and ulceration of the stomach 17-19 h after of gastric ulcers (38). This procedure has been
the operation. The antiulcer agents are given adapted to testing antiulcer activity (39).
subcutaneously or intraduodenally at the time There are certain differences between steroid
of ligation of the pylorus, or orally 1 h before. ulcers and "natural" ulcers in localization,
The animals are killed 17-19 h after pyloric rate of development, and severity (40).
2 Biocomparative Assay of Anticholinergics

The antisecretory activities of anticholin- jury and finally results in gastric metaplasia.
ergics are as important as their antiulcer ac- In the presence of antral H. pylori, the gastric
tivities for their therapeutic usefulness. The metaplasia becomes colonized and inflamed.
Pavlov gastric pouch (41) with intact vagal The inflammation and infection disrupts mu-
and sympathetic nerve supply and a modified cosal defense and regenerating mechanisms,
Heidenhain pouch (421, which is essentially resulting in ulceration. The combination of in-
denervated, are prepared from dog stomach flammation, protective deficiencies, and mod-
and have been used for determining the action erate amounts of acid and pepsin may be
of drugs on gastric secretion. Histamine or a enough to induce ulceration. Several groups of
test meal is usually used as a stimulus. Similar drugs including anticholinergic agents have
methods for the preparation and use of been developed to antagonize risk factors
chronic total gastric fistulas and chronic de- causing ulcer disease. A good animal model,
nervated gastric pouches have been described which incorporates all variable causes of ulcer
for determining drug action on gastric secre- disease, is yet to be developed.
tion in rats (43-45). The muscarinic receptors of the parietal
There are a significant number of reports cells are of the M1 subtype. The specific anti-
in which antisecretory and antimobility ef- cholinergic agents for M1 receptors are con-
fects of anticholinergic drugs have been eval- sidered to be effective for the treatment of ul-
uated in ulcer patients (9,46). The antisecre- cer disease (51). The muscarinic receptors on
tory potency can be measured best in the the duodenal smooth muscle are possibly of
duodenal ulcer patient in whom the acid out- the M3 subtype. Anticholinergics at M3 may
put is already high. Ability of the drug to abol- partially decrease pain of duodenal ulcers by
ish or diminish acid output under histamine decreasing the motility of the duodenum (52).
stimulation is a stringent test of activity, al-
though the test has limited physiological rele-
2.3 Mydriatic and Cycloplegic Activities
vance. The effect of the drug on the amount of
acid secreted under ordinary clinical condi- A simple and relatively accurate test for myd-
tions is the most pertinent of all tests in rela- riatic activity has been described (52). The
tion to therapeutic application. method requires mice and a binocular micro-
Despite extensive research, certain aspects scope, magnifying about 10 times and pro-
of ulcer disease are not clearly elucidated. Be- vided with a scale in the eyepiece with which
cause of the multiple processes that control to examine and measure the diameter of the
acid and pepsin secretion and defense and re- pupil of the mouse. A strong light shining into
pair of gastroduodenal mucosa, it is more the eye of the mouse must be attached to the
likely that causes of ulceration differ among microscope. The diameter of the pupil is mea-
individuals (Section 3.5). Two other factors sured at the peak effect after administration of
have been acknowledged as risk factors in the the anticholinergic agent by intraperitoneal
pathophysiology of peptic ulcers: nonsteroidal injection. The duration of the effect is also im-
anti-inflammatory drugs (NSAIDs) and Heli- portant, given that one of the most character-
cobacter pylori infection (47-50). NSAIDs in- istic and valuable properties of atropine and
duce a significant number of gastric and duo- analogous compounds is the prolonged effect
denal ulcers, possibly because of inhibition of that they produce in the eye.
prostaglandin synthesis with consequent loss Entopic pupillometry is an accurate and
of protective effects. H. pylori has been recog- practical method for measuring the size of the
nized as a risk factor in the ulcerative process, pupil in humans (53). With a Cogan entopic
similar to acid and pepsin. Duodenal ulcer is pupillometer, the normal size of the pupil and
typified by H. pylori infection and duodenitis the near and far points before and after instil-
&d possibly impaired duodenal bicarbonate lation of the drug in the conjunctival sac can
secretion in the face of moderate increases in be measured at different time intervals. The
acid and peptic activity. Increased peptic ac- amount of light entering the eye is quite small
tivity with decreased duodenal buffering ca- and the movements of the eye during the mea-
pacity possibly leads to enhanced mucosal in- surement do not interfere with the test.
Anticholinergic Drugs

2.4 Miscellaneous Anticholinergic Activities Apollo in his temple at Delphi. Here the priest-
ess of the god Pythia sat on a tripod uttering
A number of other methods are available for
incoherent words in a divine ecstacy, in reply
comparing the activities of anticholinergic
to the questions that were asked. Pythia was
agents, of which the antitremor and antisali-
intoxicated by the fumes from burning datura
vary effects are widely used. Arecoline or pilo-
leaves; her replies were interpreted by a priest
carpine may be used to induce tremor or sali-
in the form of a verse. The more common uses
vation in a suitable species that can be blocked
of datura were for robbery or conspiracy. In-
by an anticholinergic agent. There seems to be
dian courtesans were known to place datura in
good correlation between anticholinergic and
their visitors' wine, so that they could be
antitremor effects (54). Recovery of the sali-
robbed without interference. As recently as
vary gland from cholinergic block may con-
1908, there was a plan to poison the European
ceivably precede that of the gastric glands and
garrison in Hanoi in Vietnam using datura.
the two effects may therefore not necessarily
Those in the conspiracy intended to stupefy
parallel each other in duration (9).
the soldiers, and then to kill them.
The pharmacological actions of atropine
3 SOLANACEOUS ALKALOIDS and related alkaloids are intimately connected
with our knowledge of the organization and
The older anticholinergic drugs are the vari- function of the autonomic nervous system.
ous galenical preparations of belladonna, hyo- Schmiedeberg and Koppe (56) were the first in
scyamus, and stramonium, all of which are de- 1869 to focus attention on the similarity be-
rived from plants of the potato family, the tween a drug effect and electrical stimulation,
Solanaceae. The species used as drugs include when they pointed out that muscarine and va-
Atropa belladonna, one of several plants gus stimulation affected the heart in the same
known colloquially as "deadly nightshade"; fashion and the actions of both were antago-
Hyoscymus niger (black henbane); and Datura nized by atropine. Further, they recom-
stramonium (jimsonweed, jamestown weed, or mended atropine as an antidote for mushroom
thorn apple). The active principles in all these poisoning. As early as 1887, Kobert and Sohrt
plants consist mostly of (-)-hyoscyamine, with (57) provided experimental proof for both sim-
smaller variable amounts of (-)-scopolamine ilarities and dissimilarities between atropine,
(hyoscine).Atropine is (?)-hyoscyamine. and scopolamine.
Atropine was isolated by Mein in 1831 (58),
3.1 History and since then the synthesis of both atropine
The poisonous nature of solanaceous alkaloids and scopolamine has been achieved (59,60). A
has been known for many centuries (55). The biogenetic scheme for the synthesis of atro-
toxic properties of deadly nightshade were ev- pine-like alkaloids in datura species starting
ident when children ate the blackberries, from ornithine has been described (61).
which looked attractive in a fall hedgerow in
England. The children became delirious and 3.2 Chemical Structure
their eyes had widely dilated pupils. The
deadly nightshade was used by the poisoners All the solanaceous alkaloids are esters of the
of the Middle Ages to induce obscure and often dicyclic amino alcohol 3-tropanol (tropine, 1).
delayed poisoning. Therefore, Linn6, in 1753, Atropine is an ester of (+)-tropic acid and tro-
named the shrub Atropa belladonna after At- pine. In scopolamine the organic base is sco-
ropos, the oldest of the Three Fates, who cuts
the thread of life. "Belladonna" does not refer
to Atropos, who is considered as a grim and

awesome female. but to the Italian name

("handsome women") of the plant, which was
used by Venetian ladies to give them dilated
pupils ("sparkling eyes").
Datura has an ancient history, for it is said
to have been used a t the oracular shrine of
3 Solanaceous Alkaloids 121

pine. Scopine differs from tropine in having an In tropine, the axially oriented hydroxyl
oxygen bridge between C-6 and C-7. group, trans to the nitrogen bridge, is desig-
There are some other alkaloids that are nated as a! or anti, and the alternate, equato-
members of the solanaceous alkaloids (e.g., rially oriented hydroxyl group as P or syn. It is
apoatropine, noratropine, belladonnine) but generally considered that cycloheptane is fixed
they are not of sufficient therapeutic value to through an -N(CH3)-bridge in the struc-
be discussed in this context. tures of tropine and pseudotropine. Therefore,
The carbon cr to the carboxyl group of tropic a chair conformation is ascribed to the piperi-
acid is asymmetric and is easily racemized dine ring system in tropine and pseudotro-
during the isolation of the solanaceous alka- pine. However, there is only a seeming differ-
loids. Atropine and atroscine are racemic ence between the two conformations of
forms. The corresponding lev0 isomers, (-1- tropane derivatives (66). The tropane system
hyoscyamine and (-)-scopolamine (hyoscine), can be considered with equal justification as a
occur naturally in the solanaceous plants. piperidine twisted through the -CH2CH2-
The absolute configuration of (-)-tropic bridge or as a cycloheptane fixed through an
acid has been established by its correlation -N(CH3)-bridge. When the tropane system
with (-)-alanine (62). According to the Cahn- is structured by the chair form of piperidine, it
Ingold-Prelog convention (631, natural (- )- also represents the boat form of cycloheptane.
tropic acid possesses the (5')configuration. Ac- Similarly, the boat form of piperidine is at the
cordingly, (-)- hyoscyamine and (-)-hyocine same time a chair form of the cycloheptane
have an (S) configuration (64). ring. Therefore, it may be assumed that both
The piperidine ring system can exist in two forms are present in a state of equilibrium
principal conformations. Its chair form has (65a)65. Based on the conformations of the
the lowest energy requirement. However, the tropane system, the structure of atropine (4)
alternate boat form can also exist, because the can be represented by (5)and (61, of which (5)
energy barrier is not great. The formula of is more generally accepted.
3-hydroxytropine (1) indicates that, even
though there is no optical activity because of H
the plane of symmetry, two stereoisomeric H2C-C- CH2 CH20H
forms, tropine (2) and pseudotropine (31, can NCH3 CHOCOCH
exist because of the rigidity imparted to the I I I
molecule through the ethane chain across the H2C-C- CH2 C6H5
1,5 positions (65a).


Anticholinergic Drugs

P - 7 - I I
- H, F6H5
\ c-c- I I

The amino alcohol derived from scopol- through its quinine salt and the separated en-
amine (7), that is, scopine (8), has the axial antiomorph~can be converted into (+)- and
orientation of the 3-OH group but in addition (-)-hyoscyamines.
has a P-oriented epoxy group bridged across (-)-Scopolamine (hyoscine) is isolated
the 6, 7 positions. from the mother liquor remaining after the
isolation of hyoscyamine, and is marketed as
H H its hydrobromide. Scopolamine is readily race-
CH2 mized to atroscine, when subjected to treat-
NCH3 CHOH ment with dilute alkali.
I 0
C-C-CH2 The synthesis of scopolamine differs from
H H OH that of atropine in the synthesis of the amino
alcohol, scopine portion of the molecule. Fod6r
and coworkers (60, 73, 74) have synthesized
scopine starting from 6-P-hydroxy-3-tropanone.
3.3 Preparative Methods Esterification of scopine with 0-acetyltropyl
Conventional methods of alkaloid isolation are chloride and mild hydrolysis of the acetylsco-
used to obtain a crude mixture of atropine and polamine give scopolamine.
(-)-hyoscyamine from the plant products.
This crude mixture of alkaloids is racemized to 3.4 Molecular Factors in the Absorption,
atropine by refluxing in chloroform or by Fate, and Excretion of Atropine and
treatment with cold dilute alkali (67). Related Compounds
Atropine can be synthesized from tropi-
none and tropic acid as starting materials. The belladonna alkaloids are absorbed rapidly
Tropinone can be prepared by Robinson's syn- after oral administration (75). They enter the
thesis (68) and reduced under proper condi- circulation when applied locally to the muco-
tions to tropine. (?)-Tropic acid can be pre- sal surfaces of the body. Atropine absorbed
pared from ethyl phenylacetate (69, 70) or from inhaled smoke of medicated cigarettes
acetophenone (71). The 0-acetyl derivative of can abolish the effects of intravenous infusion
tropyl chloride reacts with tropine to yield O- of methacholine in humans. The transcon-
acetyl of atropine hydrochloride, from which junctival absorption of atropine is consider-
the acetyl group hydrolyzes spontaneously in able. About 95% of radioactive atropine is ab-
aqueous solution (72). sorbed and excreted following subconjunctival
One of the commercial sources for (-)-hy- injection in the rabbit. The total absorption of
oscyamine is Egyptian henbane (Hyoscyamus quaternary ammonium derivatives (Section
muticus) in which it occurs to the extent of 3.5) of the alkaloids after an oral dose is only
0.5%. Another method for extraction of the about 25%. The liver, kidney, lung, and pan-
alkaloid uses Duboisia species. It is prepared creas are the most important organs that take
from the crude plant material in a manner up the labeled atropine. The liver probably ex-
similar to that used for atropine and is purified cretes metabolic products of atropine by way
as the oxalate. (?)-Tropic acid can be resolved of bile into the intestine (in mice and rats).
3 Solanaceous Alkaloids

Carbon dioxide
(+ noratropine 2%)

Rabbit liver
in vitro
1I Rabbit,
guinea pig

guinea pig
tropic acid

Rat liver
in vitro
(25%) Man,
atropines (10%)
- Tropicacid %)


p-Hydroxyatropine (2%) - m, p-Dihydro)

Figure 3.2. Metabolism of atropine and i t s variations in different species.

Because most of the synthetic antispas- At least four types of molecular modification6
modic and antiulcer agents are administered occur for the urinary excretion of atropine
orally, their absorption through the gastroin- (Fig. 3.2). Cleavage of the ester bond takes
testinal tract limits their therapeutic useful- place in the rabbit and the guinea pig (84),
ness. There are striking diferences in the ab- whereas para and meta hydroxylation of the
sorption of tertiary amines and quaternary benzene ring of tropic acid occurs in the mouse
ammonium compounds (76-78). The tertiary and the rat (80, 82). The tropine moiety of
amines (e.g., noroxyphenonium, mepiper- atropine is also chemically modified for excre-
phenidol; Section 4) are absorbed completely tion in man and mouse and, though unidenti-
from rat intestinal loops. The maximal ab- fied, "tropine-modified atropines" are ex-
sorption of the corresponding quaternary am- creted in humans and in mouse (83). Tropic
monium compounds is about one-fifth of the acid itself does not undergo metabolic alter-
total dose. The poor absorption of quaternary ation for urinary excretion in all species men-
ammonium compounds may be partly attrib- tioned above. The metabolic conversions of
utable to the positive charge that promotes tropine itself are not fully investigated. How-
the formation of a nonabsorbable complex ever, demethylation of atropine- N-14CH3(or
with mucin. The ready absorption of tertiary tropine- N-14CH3)has been reported in a num-
amines may be explained partly by their per- ber of species with exhalation of 14C0, (90).
meability through lipid membranes (79). The possible metabolic changes of atropine are
Considerable species variations have been schematically represented in Fig. 3.2.
reported for the metabolic detoxification of at- After intravenous injection of atropine, ap-
ropine in mammals (80-91). These differences proximately 25% of the dose is excreted in
seem to be more quantitative than qualitative. mouse urine as atropine, more than 50% as
Anticholinergic Drugs

conjugates with glucuronic acid, and the re- tropic acid. In this way a series of tropeines
maining 20-25% as intermediate oxidation have been synthesized, among which a num-
products (probably p-hydroxyatropine and ber of active compounds have been found (86-
3,4-dihydroxyatropine)and "tropine-modified 92). Of the tropeines, mandelyl tropeine (9,
atropines." Rats are known to metabolize at-
ropine in a manner similar to that in mice. In
humans, about 50% of the administered dose
of atropine is excreted unchanged in the urine
and about 33% as unknown metabolites that
are esters of tropic acid. Neither hydroxyla-
tion of the tropic acid moiety nor glucuronide
formation has been demonstrated in humans
(83). Only less than 2% appears as tropic acid
in urine. homatropine), has survived as a thrapeutic
It has been known for more than a centurv agent to the present.
that rabbits can tolerate large quantities of Methylatropine nitrate (10)(or bromide) is
atropine (84, 85). The cause of this observa- a synthetic quaternary derivative of atropine.
tion is the ability of the serum of some, but not Atropine oxide (atropine N-oxide) is known as
all, rabbits to hydrolyze atropine into tropic a genatropine (11)and may be prepared by oxi-
acid and tropine. The hydrolysis is attributed dation of the alkaloid with hydrogen peroxide.
to an enzyme, atropinesterase, which is found
in most other tissues as well as the serum of
these rabbits. The highest activities are found
in the liver and intestinal mucosa; only the
brain and aqueous humor of the eye contain
no enzyme. The enzyme is also found in the
liver of the guinea pig and accounts for the
appearance of tropic acid in the urine of the
rabbit or the guinea pig, but not other ani-
mals, following the administration of atro-
The presence of atropinesterase in rabbits
is inherited through an incompletely domi-
nant gene (84). This gene is associated with
another gene that influences the color of the
fur, causing "extension of black pigment in the
The derivatives of scopolamine (7) pre-
pared by similar methods are available com-
Atropinesterase can also hydrolyze homat-
mercially. These include methscopolamine
ropine and scopolamine. This enzyme is ste-
bromide (121, methscopolamine nitrate, and
reospecific for (S)-(- )-hyoscamine, which is
genoscopolamine (scopolamine N-oxide, 13).
split; the more inert (R)-(+) isomer is not
readily hydrolyzed (84).
3.5 Semisynthetic Derivatives / I I I
of Solanaceous Alkaloids 0 N+(CH3)2 CHOCOCHCsH5. Br-
\ I I
Early attempts to modfy the atropine mole- HC-CH CH2
cule (4) were aimed at converting the solana-
ceous alkaloids containing the tertiary nitro-
gen into quaternary ammonium compounds
and N-oxides. Later developments have been Homatropine (9) is prepared by evaporat-
to retain the tropine (or scopine) portion of the ing tropine with mandelic and hydrochloric
molecule and substitute various acids for acids. Homatropine methylbromide (14) may
3 Solanaceous Alkaloids


ment of bronchospasm associated with chronic

obstructive pulmonary disease. Because it is ad-
be prepared from homatropine by treating it ministered as an aerosolized preparation, its
with methyl bromide. droplets are deposited in upper airways and
Quaternization may or may not increase all produce bronchodilation within minutes.
types of anticholinergic activity significantly. Only less than 5% of the drug enters the
However, there are certain practical advan- systemic circulation. Ipratropium is an exam-
tages to quaternization. The quaternary am- ple of developing a useful drug for a specific
monium derivatives usually penetrate the purpose by minor molecular modification of
CNS less readily than the corresponding ter- atropine.
tiary amine analogs. Therefore, quaterniza- The N-oxides are converted to the corre-
tion serves as a useful technique to avoid or sponding tertiary bases in vivo. Atropine N-
minimize the side effects caused by the stimu- oxide and scopolamine N-oxide are slowly re-
lation of the central nervous system by the duced to atropine and scopolamine in the
tertiary amines, when the drugs are used for animal body. Therefore, N-oxidation is a con-
their peripheral actions. When a tertiary alka- venient technique for prolonging the duration
loidal base is converted to the quaternary of the action of the alkaloidal bases. The NL
form, the latter is also less readily absorbed oxides are said to be less toxic.
through the intestinal wall (93, 94; Section Solanaceous alkaloids have a wide and vari-
3.2). This is not a disadvantage when the drug able spectrum of anticholinergic activities and
is used for its effects in the gastrointestinal are widely used in therapeutics. The various
tract. However, if the drug is used for its sys- derivatives of atropine, scopolamine, and
temic or central actions, the effect becomes homatropine are listed in Table 3.2. Because
erratic and unpredictable because the absorp- of their chemical differences and the resulting
tion is poor after oral administration. The ter- biological interactions, different derivatives
tiary amines are preferred for ophthalmic use are preferred for antispasmodic, antisecre-
because they penetrate the cornea better than tory, mydriatic, or central effects. Scopol-
their quaternary ammonium derivatives. amine produces the same type of depression of
However, when a drug (e.g., atropine) has a the parasympathetic nervous system as do at-
long-lasting mydriatic effect, its recovery pe- ropine and homatropine, but it differs mark-
riod can be shortened by quaternization. edly from atropine in its action in the central
Therefore, the selection of the type of the de- nervous system. Whereas atropine stimulates
rivative (Table 3.2) depends on the specific the CNS, causing restlessness, scopolamine
purpose for which it is used, the mode of its can act dose dependently as a sedative. It also
administration, and the duration of the de- causes temporary amnesia ("twilight sleep")
sired effect. when used along with morphine in obstetric
Ipratropium bromide (15)is a useful qua- and gynecologic procedures. For a detailed dis-
ternary derivative of atropine (95, 96). It is cussion of the anticholinergic activities of so-
marketed as a metered-dose inhaler for treat- lanaceous alkaloids and their related com-
Anticholinergic Drugs

pounds, the standard textbooks or review simpler to synthesize a fairly complex mole-
in pharmacology should be consulted (75,97- cule from two halves by esterification than by
99). any other method. Therefore, many esters of
amino alcohols and carboxylic acids have been
synthesized as atropine substitutes, in which
the structures of either one or both halves
have been changed. For example, in homatro-
Although atropine and its related alkaloids are
pine, the tropic acid moiety has been replaced
potent anticholinergics, they have a wide spec-
by mandelic acid. The amino alcohol moiety
trum of pharmacological activities. Therefore,
(tropine, 1)of atropine has afforded unusually
therapeutic administration of these alkaloids
rich opportunities for the synthesis of anticho-
to elicit a particular desired activity invariably
linergics (Fig. 3.3). Scission of its piperidine
results in some undesirable side effects. For
ring at point X gives the derivatives of hy-
this reason, the search for compounds possess-
droxyalkylpyrrolidines (16),and scission of its
ing one or another of the specific desirable ac-
pyrrolidine ring at point Y makes it possible to
tions has been an active field of investigation
proceed to derivatives of 4-hydroxypiperidine
in medicinal chemistry. The ideal specificity of
(17).The scission of both rings at Z leads to
action has not been attained in these at-
dialkylaminoalkanol derivatives (18). Fur-
tempts; perfect atropine substitutes with pre-
thermore, simplification and alteration of
dominant antispasmodic, antisecretory, or cy-
these three groups of amino alcohols has re-
cloplegic actions have yet to be synthesized.
sulted in the synthesis of esters containing
However, some progress has been made since
structural features more or less similar to
the discovery of multiple subtypes of func-
those of atropine.
tional muscarinic receptors (MI-M5) and the
Antagonists of acetylcholine often have
cloned muscarinic receptors (m,-m,) have
chemical structures resembling that of acetyl-
been identified (Table 3.1). Several antago-
choline, although they differ from it by greater
nists, which show selectivity to one subtype of
complexity of the molecule and higher molec-
muscarinic receptors over others, have been
ular weight. Acetylcholine is a quaternary am-
introduced and they have become useful in the
monium compound; atropine and tropine con-
delineation of subtypes of muscarinic recep-
tain a tertiary nitrogen. Therefore, a number
tors in various tissues. Some of these agents
of atropine-like compounds having quater-
may become useful as antiulcer agents, anti-
nary nitrogen atoms have been synthesized.
spasmodics, or mydriatics.
In some of them, the acetyl group of acetylcho-
line has been replaced by acid moieties con-
4.1 Analogs of Atropine
taining blocking groups (e.g., diphenylacetic
The synthetic anticholinergic drugs can be acid).
considered as analogs of atropine or antago- The principles used in the design of antime-
nists of acetylcholine. Most of these com- tabolites have been applied to synthesize atro-
pounds were designed using broad principles pine-like compounds. The ester group in atro-
of molecular modification such as (1)scission pine-like compounds has been replaced by a
of the atropine molecule into simpler mole- thioester, an amide, an ether group, or a chain
cules containing the essential pharmacophoric of methylene carbons (Table 3.3).
groups; (2) molecular modification by intro- All synthetic anticholinergic agents have
ducing "blocking" moieties into cholinergics; some structural features in common. In most,
and (3) changes in other anticholinergics us- the molecule has bulky "blocking moieties,"
ing principles of bioisosterism. often cyclic radicals, linked by a chain of atoms
The structure of atropine has been the ba- of limited length, to a positively charged
sis for a large number of synthetic anticholin- m i n e nitrogen (Fig. 3.4). The length and
ergic agents. However, no significant changes structure of the main chain have considerable
have been made to affect the "ester-complex" influence on the anticholinergic activity of the
grouping because of atropine-like properties. substance. At the same time the chemical na-
Another probable consideration is that it is far ture of the main chain determines the class of
4 Synthetic Anticholinergics

p H 3
R"' Figure 3.3. "Scissions" of tropane
(18) ring.

organic substances to which a given substance However, several examples from drugs used as
belongs. Therefore, the classification of syn- therapeutic agents are discussed at appropri-
thetic anticholinergics in Table 3.3 is based on ate places in the following pages. These com-
the structure of the main chain of the mole- pounds may be classified differently, and the
e, taking into consideration wherever nec- same compound may be placed in more than
ary the presence or absence of any addi- one group. Each one of them may be consid-

It is beyond the scope of this text to consider ergic activities among a series of structurally
all compounds that belong to each group. related compounds whose structure-activity

Characteristic Group Atoms in the Pharmacophoric Groups

in the Main Chain Chain that May Be Present

C C - 0 - C -OH
Thioester CC--S-C -OH
Amide -C-N-€ -OH
Carbarnate )N-C--O--C
Alkane --C-C-C--
(a)Amino alcohols -OH
(b) Amides -4ONH,
Anticholinergic Drugs

Ester end Onium head sium channels. Acetylcholine opens potassium

channels in the heart and causes hyperpolar-
ization and a reduced rate of firing of the nodal
tissue. In many tissues, calcium channels are

-- -
opened and probably intracellular calcium is
mobilized and, like many other transmitters,
acetylcholine increases the turnover of phos-
phoinositides. Therefore, there is much expec-
tation that selective agents will be found
among muscarinic antagonists that will be
Acyl Ester Alkamine Quaternary
radical group chain amino function useful to block one particular physiological or
Acetylcholine (19) biochemical response to acetylcholine. Thus,

- -*
several agents have been synthesized that
Cyclic Esteratic Cationic have structural features similar to those of at-
radical group portion ropine-like agents, cyclic blocking moieties
linked by a chain of atoms of limited length to
,H a positively charged nitrogen atom.
Based on the cyclic-blocking moieties and
other substituent groups, subtype-selective
muscarinic antagonists can be classified into
eight groups: (1)tricyclic benzodiazepines, (2)
benzothiazepines, (3) quinuclidines, (4) poly-
methylene tetramines, (5) indenes, (6) sila-
difenidols, (7) diphenylacetyloxy derivatives,
~ a i chain
n and (8) himbacine akaloids.
Atropine (20)
Figure 3.4. Structural features of acetylcholine 4.2.1 Tricyclic Benzodiazepines. Sigdicant
and atropine. The asymmetric carbon in atropine is side effects of tricyclic antidepressants, like
marked with an asterisk (*). imipramine, are antimuscarinic effects. Ben-
zodiazepines also cause some antimuscarinic
effects like dry mouth at therapeutic concen-
relationships have been evaluated for differ-
trations. Some of the well-known anticholin-
ent types of pharmacological effects. Com-
ergic agents, Banthine, Probanthine, and
pounds with the same or similar structural
Trest, have tricyclic bulky moieties at the end
features may exhibit other pharmacological
of their molecules. Some molecular features of
effects as side effects. For example, a large
these three types of phamacological agents are
number of compounds have been synthesized
present in tricyclic pyrido-benzodiazepines.In
containing an ether link in the main chain.
these compounds, portions of benzene and
These compounds are useful as antiparkinso-
pyridine (or other rings) are fused to a seven-
nian drugs and antihistaminic agents.
membered diazepine ring in the middle. The
trycylic bulky moiety containing benzene, di-
4.2 Receptor-Subtype-Selective
azine, and pyridine rings (or other rings) at
the end of a molecule satisfies one of the re-
The muscarinic actions of acetylcholine can be quirements for an anticholinergic agent. Fur-
either stirnulatory or inhibitory. Acetylcholine ther substitutions on the imino-nitrogen atom
stimulates secretion and contraction of the have resulted in selective M1 receptor antag-
gut, but it inhibits the contraction of the heart onists that are useful as antiulcer agents.
and relaxes the smooth muscle of blood ves- Pirenzepine (21) was the first M1 receptor
sels. Acetylcholine can inhibit adenylate cy- antagonist shown to inhibit gastric secretion
clase and activate guanylate cyclase. In the (100, 101). This drug (100-150 mg/day) is
cortical neurones, muscarinic agents cause a used in several countries to decrease gastric
slow depolarization mediated by closing potas- secretion and achieve maximal rates of ulcer
4 Synthetic Anticholinergics 129

dNb 0 AX-RA 513 (24) is another analog of piren-

zepine and exhibits selectivity toward M2 re-
ceptors (104). The spatial orientation of the
protonated side-chain nitrogen atom in rela-
tion to the tricycle seems to be of major impor-
tance for Ml/M2 selectivity.

AQ-RA 741 (25) is an analog of pirenzepine
0 that exhibits higher affinity to chimeric m2
and M4 receptors than for m5 receptors (105).
VH-AH-37 (26), a pirenzepine derivative, ex-
hibits higher affinity to chimeric m5 receptors
N than to m2 receptors.

4.2.2 Benzothiazepines. These are closely

related compounds to benzodiazepines. The
nitrogen atom in the diazepine ring is re-
placed by a sulfur atom (27). Among these
healing. At these doses, incidence of dry compounds BTM-1086 was found to be an
mouth and blurred vision are not significant. M1 receptor antagonist (106). It is cis(-)-
It has a low lipid solubility and limited perme- 2,3-dihydro-3-(4-methylpiperaziny1)-2-phe-
abilty into the CNS, so it does not cause any nyl-1,5-benzothiazepin-4(5H)-onemonohy-
CNS side effects. drochloride. It inhibits acetylcholine release
Telenzepine (22) is an analog of pirenz- from parasympathetic nerves and also gas-
epine and 4-10 times more potent for inhibi- tric secretion.
tion of gastric secretion.
4.2.3 Quinuclidine-Based Antagonists. A se-
ries of achiral3-heteroaryl substituted quinu-
clidin-2-ene derivatives (28-31) was synthe-
sized by Hacksell et al. (107), who determined
their dissociation constants (K,) at different
subtypes of muscarinic receptors. Among
these compounds 2-benzoforanyl quinuclin-2-
diene exhibits the highest affinity (K,, 9.6 nM)
at M1 receptors. Its affinity at M2 (K,, 31 nM)
or M3 (K,, 59 nM) receptor is lower than that
at M1 receptor. This antagonist is well accom-
modated within the defined model (108) of ml-
receptor. The quinuclidin-2-ene ring will be
located in an area of the receptor defined by
val102, ala 160, and val385, where the quinu-
clidine ring of potent agonists bind (108).Sub-
stitution of the benzofuranyl group (28) by
benzothienyl(29), benzoxzolyl(30), or benzo-
AF-DX-116 is an analog of pirenzepine that thia-zoylyl(31) group decreased the affinity at
differs markedly in its profile of muscarinic the M1 receptor (Table 3.4). There is a good
activities (102,103). It has greatest affinity for correlation between the magnitude of the elec-
cardiac M2 receptors. Its cardioselectivity is trostatic potential in the benzene nucleus and
also observed in humans and may become use- the M1 receptor affinity. Further, future work
ful in sinus bradycardia and AV block of vagal may yield more selective M1 antagonists that
origin. will be useful in the treatment of ulcers.
Anticholinergic Drugs

(21) (pirenzepine) (23) (AF-DX 116) (24) (AQ-RA 513)

(25) AQ-RA 741

(26) UH-AH 37 (29)

4 Synthetic Anticholinergics

Table 3.4 K , Values of 2-R-Quinuclidin- Table 3.5 Methoctramine-Related

2-emsat Muscarinic Receptors Tetramines and Their Selectivities at M2
and M3 Subtypes of Muscarinic Receptorsa
Ki (values)"
P& Selectivity
R Group MI M2 M3 Ratiob

Benzofuranyl 9.6 31 59 Antagonist M2 M3 M2M3

Benzottienyl 81 270 420 Methoctramine" 7.78 6.28 32"
Benzoxazolyl 100 400 720 Tripitramine" 9.69 6.50 1550"
Benzothiazoyl 170 600 1100 4-DAMP 8.53 9.19 0.22~
"Reciprocals of K , values give relative affinities at the "Test system for M2 receptors: guinea pig left atria.
receptors. Summarized from Hacksell et al. (107). Test system for M3 receptors: guinea pig ileum.
bThe selectivity ratio is the antilog of the difference
between pA, values on two different systems.
'Data from Melchiorre et al. (109).
dData from Tumialti et al. (110).

tetramine backbone. Among a series of tetra-

mines, tripitramine (33)is a potent and selec-
tive M2 receptor antagonist (Table 3.5).

4.2.5 lndene Derivatives. Dimethylpyrin-

dene (Dimethindene, 35) was first introduced
as an H1 receptor antagonist. Subsequently, it
was found to be an M2 receptor antagonist.
Because of the presence of asymmetric carbon
in the molecule, it occurs in two optical forms.
In general, (S)-dimethindene is more potent
than (R)-enantiomer at muscarinic receptor
subtypes MI, M2, and M3. However, the ste-
reoselectivity (31- to 41-fold) is greatest at M2
rece~tors(Table 3.6).
A . W-Dimethindene
. . is
4.2.4 Polymethylene Tetramines. Several more specific for muscarinic receptors than at
polymethylene tetramines were developed as receptors of other biogenic m i n e s (norepine-
antagonists of the M2 receptor (109, 110). pinephrine, dopamine, and 5-HT). It pene-
Among these, methoctramine is a prototype trates the blood-brain barrier in humans and
compound (32). The selectivity and affinity of
methoctramine-like compounds at M2 recep- Table 3.6 Activities of Enantiomers
of Dimethindene at Subtypes
of Muscarinic Receptors


Test System
Rabbit vas deferensb
Rat duodenumb
Guinea pig atria
Rabbit vas deferens
pA, Values
of Isomers
tors are dependent on a tetramine backbone M3 Guinea pig ileum 5.61 6.92
and the nature of substituents on the terminal M3 Guinea pig trachea 5.59 6.96
nitrogens (33,34).This selectivity is improved
"Different selective agonists were used to stimulate the
by introduction of N-methyl groups into the receptors.
tetramine backbone and introduction of a tri- bSome test systems contain more than one subtype of
cyclic system on the terminal nitrogens of the muscarinic receptor.
Anticholinergic Drugs

(112, 113). HHSID shows a 15- to 30-fold

higher antimuscarinic potency at M3 recep-
therefore may become a valuable tool in Alz- tors of guinia pig ileum and urinary bladder
heimer's disease or evaluation of M2 receptors than at M2 receptors of the rat heart and vas-
of the CNS by PET studies. cular endothelium.

4.2.6 Sila-difenidols. Studies on antocho- 4.2.7 Diphenylacetyloxy Derivatives. Bar-

linergic agents of procyclidine (Kemadrin, low and his collaborators (114) synthesized
Table 3.3) and defenidol type have shown several muscarinic antagonists and tested
that substitution of the central carbon atom them at the muscarinic receptors in the heart
(R3--€-OH) by the silicon atom (R3-Si--OH) and the smooth muscle. One of these com-
leads to drugs with increased antimuscarinic pounds, 4-[(diphenylacetyl)oxy]-1'1-dimethyl-
potency and increased selectivity for M3 re- piperidium (CDAMP, 37) was about 10 times
ceptors (36).Hexahydrosiladifenidol (HHSID) more potent on M3 receptors of the smooth
and its p-fluoro-derivative have been used to muscle than on M2 receptors of the heart
characterize M3 receptors in smooth muscle (115).It has become very useful to identify M3
5 Structure-Activity Relationships 133

q €{I: CH-C-0
activity and higher Kd (181 nM).It appears
that himbacine is a potent muscerinic antago-
nist at M2 or M4 receptors compared to M1 or
M3 receptors (116,117).

d II


Although atropine-like agents are antagonists

of acetylcholine at one type of cholinergic re-
ceptor (muscarinic receptor) that is specific for
activation by L(+)-muscarine,they may dem-
in several tissues, especially smooth muscles onstrate many other pharmacological proper-
of trachea, ileum, vascular tissue, and cilia of ties (ganglionic blocking; neuromuscular
different species. blocking; musculotropic, central stimulant, or
depressant activities). The following discus-
4.2.8 Himbacine. This akaloid has a tricy- sion of the relationships of structure to activ-
clic structure (38).It is considered to be selec- ity is limited to their inhibitory actions at the
tive for cardiac M2 receptor (116). However, it muscarinic receptors. Certain structural fea-
tures are common in many anticholinergic
0 agents that have been synthesized and evalu-
ated pharmacologically (Fig. 3.4). Some of
these features also appear in cholinergics (19).
A typical atropine-like anticholinergic agent
(20) contains a cationic head and a heavy
blocking moiety (cyclic groups), which are con-
nected by a chain of atoms of definite length
(118-124). Their molecules include essential
constituent groups (cationic head, cyclic radi-
cals) as well as nonessential but contributing
anchoring groups (e.g., hydroxyl). The steric
factors that are related to the essential groups
significantly influence the anticholinergic ac-
(38) Himbacine tivity. Several anticholinergic agents incorpo-
rating the above structural features are listed
in Table 3.7.
binds to all five cloned muscarinic receptor
subtypes in the following order of potencies
5.1 Cationic Head
(117):hM2 = hM4 > hM3 > hM1 > hM5. Its
K, values at these receptors are 4, 7, 59, 83, The cationic head is an essential group in a
and 296, respectively. It is a potent blocker of large number of anticholinergic and cholin-
oxotremorine-induced and muscarinic recep- ergic compounds. Ordinarily, this is a substi-
tor-mediated cyclic AMP inhibition in rat stri- tuted ammonium group or, less frequently, a
atum (K,,4.4 nM) and N1E-115 neuroblas- sulfonium or a phosphonium group. The
toma cells (Kd,10.6 nM) responses, which are mechanism of the cholinergic or anticholin-
considered to be mediated by M4 receptors. It ergic action of substances has long been linked
inhibits oxotremorine-induced acetylcholine to such cationic groups (118-124).It is reason-
release from rat hippocampal tissue (K,, 8.6 able to assume that the cationic head with its
nM). The subtype of muscarinic receptor in- positive charge is attracted by the negatively
volved in this response is possibly the M2 or charged field (anionic center) of the musca-
M4 type. At the postsynaptic putative M1 and rinic receptor. Thus, the cationic head seem-
M3 receptors involved in the phosphoinositide ingly starts the process of the adsorption of the
turnover in the rat cortex, himbacine has low substance at the receptor. Following the at-
Table 3.7 Synthetic Anticholinergics (Atropininic Agents)
Selected Reference
Nonproprietaqy Proprietary for Synthetic
Name Names Chemical Name of Salt Structure of Base Procedures
Tertiary Amines-Characteristic Group in the Main Chain: Ester
Adiphenine Trasentine 2-Diethylaminoethyldiphenyl- (C6H5)2CHC02CH2CH2N(C2H,), 125,126
acetate hydrochloride
Amprotropine Syntropan 3-Diethylamino-2,2-dimethyl-
propyl tropate phosphate

Pavatrine 2-Diethylaminoethyl-9-

Cyclopentolate USP Cyclogyl P-Dimethylaminoethyl

phenylacetate hydrochloride

Dicyclomine NND Bentyl 2-Diethylaminoethylbicyclo-

0 d
If: If:
Table 3.7 (Continued)
Selected Reference
Nonproprietary Proprietary for Synthetic
Name Names Chemical Name of Salt Structure of Base Procedures
Characteristic Group in the Main Chain: Alkene
Diphemanil NF Prantal 4-Diphenylmethylene-1,l- 166

Eucatropine Euphthalmine
€ Nf(CH3)2

piperidyl) mandelate
-.L C6H5CH(OH)C02

Oxyphencyclimine Dariwn, 1-Methyl-1,4,5,6-tetrahydro-

ND Vio-Thene 2-pyrimdylmethyl a-cyclo-

Piperidolate NND Dactil 1-Ethyl-3-piperidyl diphenyl-

acetate hydrochloride (CsHd2CHC03

Pipethanate Sycotrol 2-(1-Piperidino)ethyl benzilate
hydrochloride (C6H5)2C(OH)C02CH2CH2N
Quaternary Ammonium Compoundsdharacteristic Group in the Main Chain: Ester
Glycopyrrolate ND Robinul 3-Hydroxy-1,l-dimethyl-
pyrrolidinium bromide

Mepenzolate ND Cantil N-Methyl-3-piperidyl benzilate 138,139

methylbromide (CGH~)ZC(OH)C~Z

Methantheline NF Banthine P-Diethylaminoethyl 129


Oxyphenonium NND Antrenyl Diethyl(2-hydroxyethy1)-


Penthienate NF Monodral 2-Diethylaminoethyl

glycolate methobromide
Table 3.7 (Continued)
Selected Reference
Nonproprietary Proprietary for Synthetic
Name Names Chemical Name of Salt Structure of Base Procedures

Pipenzolate NND Piptal N-Ethyl-3-piperidyl benzilate
methobromide (CGH~)~C(OH)C~Z
Nt CH3

Poldine Nadon 2-Hydroxymethyl-1,l-di-

methylsulfate benzilate

Propantheline USP Pro-Banthine p-Diisopropylmethylaminoethyl


Valethamate ND Murel 2-Diethylaminoethyl-3-methyl- CH3CHCHC02(CHZ)
2-phenylvalerate 1
methobromide C6H5

Characteristic Groups in the Main Chain: Thioester, Amide, or Carbarnate

Thiphenamil Trocinate p-Diethylaminoethyldiphenyl- (C6H5)2CHCOSCH2CH2N(C2H,),
thiolacetate hydrochloride
Tropicamide ND Mydriacyl N-Ethyl-2-phenyl-N-
(4-pyridylmethyl) hydracryl-
Dibutoline NND Dibuline Bis[dibutylcarbamate of NC02CH2N'(CH3),C2H5 151,152
ethyL(2-hydroxyethy1)- /
dimethylammoniumlsulfate C4H9

Characteristic Groups in the Main Chain: Alkane

Amino alcohols
Hexocyclium ND Tral N-(p-Cyclohexyl-p-hydroxy-p-
piperazine methylsulfate

w Mepiperphenidol Darstine 5-Methyl-4-phenyl-141-
hexanol bromide
Tricyclamol NND Elorine, l-Cyclohexyl-l-pheny1-3-
Tricoloid pyrrolidino-1-propanol

Tridihexethyl NF Pathilon
140 Anticholinergic Drugs

Table 3.8 Basicity and Anticholinergic Activity of Substituted Aminoethyl

Esters of Benzilic Acid
Doseb Required to Eliminate the
Van der Effects of Arecoline in Mice,
v o w
Basicity, Radiusa of
R PK, N-R (A) Salivation Tremor
H 8.08 2.25 5.0 6.8 (6.7)
CH3 10.87 3.09 0.48 -
OH 4.68 3.01 94.8 284.5
0CH3 10.18 4.37 4.5 -
"The van der Wads' radius of N- R bond gives an estimate of the steric volume and, therefore, steric hindrance for the
interaction of the cationic head at the muscarinic receptor.
bDosesare calculated from the values reported by Kuznetsov and Golikov (65).

traction of the oppositely charged groups, the and partition between aqueous and organic
weaker dipole-dipole, hydrophobic, and van phases. Alkylation of the oxygen atom con-
der Valls forces go into action; if there are verts the N-oxides into typical quaternary am-
many of them, especially in the case of anti- monium compounds. By this procedure, both
cholinergics, they contribute to the stability of the basicity and anticholinergic activity (Ta-
the drug-receptor complex. In such an interac- ble 3.8) of the substance increase sharply.
tion not only the charge of the cation head but The influence of a steric factor is more evi-
also its size and shape are of vital importance. dent among compounds in which the size of
The basicity of different amino derivatives, the substituents at the nitrogen atom is varied
and consequently the degree of their ioniza- both in the series of anticholinergic and cho-
tion at physiological pH, varies over a broad linergic compounds. Progressive replacement
range. The more ions of the anticholinergic of the N-methyl groups of acetylcholine with
ammonium compound or amine in solution, ethyl groups leads to a stepwise reduction in
the greater the probability of their interaction muscarinic activity (167). Likewise, maximal
with the anionic center of the muscarinic re- anticholinergic or blocking activity (Table 3.9)
ceptor to form the drug-receptor complex. In is obtained by replacing the N-methyl groups
addition, the stability of the drug-receptor of P-dimethylaminoethyl benzilate methyl-
complex that has formed should depend on the chloride with ethyl groups (119). Further in-
basicity, given that the rate of hydrolysis of creases in size to butyl or larger alkyl groups
salts is inversely proportional to the base reduce or abolish the activity (119, 168-172).
strength. Therefore, it seems that for stimulant activity,
Thus, high basicity should favor the anti- the small cationic head must fit into a definite
cholinergic activity of a substance. Although space and must aid the neutralization of the
the logic of this conclusion is simple, its proof charge of the anionic site of the receptor. The
involves great difficulties. In a series of anti- inhibitory action is obtained when large
cholinergics, transition from one derivative to enough groups are substituted on the cationic
another is associated with stepwise changes in portion to prevent close contact with the re-
basicity, as well as steric factors. In this re- ceptor and hence the neutralization of the
spect the N-oxides, which are obtained charge (173,174). Thus, the cationic portion of
through the oxidation of the corresponding the blocking agents provides the electrostatic
tertiary amines, have lower basicities and also forces necessary to orient the molecules to-
lower anticholinergic activities (164-166). ward the receptor and hold them in place.
The N-oxides are closer to the corresponding The anticholinergic activity depends not
quaternary ammonium compounds than to only on the number and the molecular weight
the tertiary ammonium ions in steric respect of the alkyl radicals that are connected to the
5 Structure-Activity Relationships 141

Table 3.9 Influence of the Number, Size, and Structure of Alkyl Groups in the Cationic Head
on the Anticholinergic Activity

Name or Structure of Compounda Activity

Compound Ratiob
Pair Series A Series B Test System B/A Ref.

1 RN(CH,), RN(C,H,), Cat: salivation 1.63 119

Cat: blood pressure 2.09
+ + Mouse: mydriasis 0.45
2 RN(CH3),nC3H7 RN(CH,),isoC,H, Cat: salivation 2.00 119
Cat: blood pressure 2.38
+ + Mouse: mydriasis 4.09
3 RN(CH3),nC3H7 RN(CH,),nC,H, Cat: salivation 0.49 119
Cat: blood pressure 0.52
+ + Mouse: mydriasis 0.63
4 RN(CH,),C,H, RNCH3(C,H5), Cat: salivation 1.06
(lachesine) Cat: blood pressure 1.31
+ + Mouse: mydriasis 0.60
5 RNCH,(C,H,), RN(CZHJ3 Cat: salivation 1.00 119
Cat: blood pressure 0.79
Mouse: mydriasis 1.33
6 Atropine ()NCH,) N-Ethylnoratropine Cat: blood pressure 0.04 179
7 Homatropine N-Isopropylnor- Cat: blood pressure 0.12 179
8 Atropine N-Allylnoratropine Cat: blood pressure 0.04 180
Rat: mydriasis 0.13
aR = (CsH5)2C(OH)C02CHzCH2-.
*In Tables 3.93.11, 3.13, and 3.15 the influence of the molecular modification on the pharmacological activity is
expressed as activity ratios. An activity ratio represents the ratio of the relative molar activities of two substances, whose
activities are compared with a standard substance. A ratio of 1.0 indicates that the molecular modification that converts the
compound in series A to the corresponding compound in series B does not change the pharmacological activity. An activity
ratio of greater than unity indicates that the molecular modification has increased the activity; when it is less than unity the
molecular modification has decreased the activity.

nitrogen atom but also on their structure. In Besides the charge on the cationic head of
contrast to di-n-propylamino derivatives, di- anticholinergics (and cholinergics), other fac-
isopropylamino derivatives have an anticho- tors seem to contribute to the interaction be-
linergic activity close to or higher than the tween the muscarinic receptor and the anticho-
activity of diethylamino derivatives (136,175- linergics. The substituents at the nitrogen atom
178). The close correlation of the activities of apparently participate actively in the process.
the diethyl and diisopropyl derivatives could This is evident from the anticholinergic action of
be related with the equal linear lengths (from the 3,3-dimethylbutyi ester of benzilic acid,
the nitrogen atom) of these radicals. (C,H,),C(OH)C02CH,CH2C(CH3)3, which con-
In the case of cyclic amino alcohols where tains no nitrogen and consequently is not ion-
nitrogen enters into the composition of the cy- ized, but which has in the corresponding posi-
cle, the optimal anticholinergic effect is pro- tion a t-butyl radical that sterically imitates the
duced not by the N-ethyl, N-isopropyl, or N- trimethylammonium group (191). A similar re-
allyl, but by N-methyl radical, as is apparent placement of a trimethylammoniumgroup with
from a comparison of the esters of tropine (Ta- a t-butyl radical in acetylcholineleads to its "car-
bles 4-6). It may be that the elements of the bon analog," CH,CO,CH,CH,C(CH,),, which
cyclic structure occupy a sufficiently large is similar to acetylcholine in its behavior toward
space besides the nitrogen atom. cholinesterase (192).
As a general rule, quaternization with a 5.2 Cyclic Moieties
small alkyl group increases activity (Table
3.10),although a few exceptions have been re- The introduction of two phenyl groups into a
ported (181, 182). molecule of acetylcholine or a cholinergic
142 Anticholinergic Drugs

Table 3.10 Differences Between the Anticholinergic Activities of Tertiary and Quaternary
Ammonium Compounds and Atropine-like Agents
Series A: Tertiary Activity
Compound Ammonium Series B: Quaternary Ratio
Pair Compounds Ammonium Compounds Test System BIA Ref.
Atropine Methylatropine Guinea pig: ileum
Mouse: mydriasis
Mouse: mydriasis
Guinea pig: ileum
Mouse: mydriasis
Tertiary analog Rabbit: intestine
of methantheline
Tertiary analog Rabbit: ileum
of penthienate Rabbit: salivation
(5)-Procyclidine Guinea pig: ileum
Mouse: mydriasis
Methyl analog Guinea pig: ileum
+ of (?I-benzhexol Mouse: mydriasis
RN(CH& Cat: salivation
Cat: blood pressure
Mouse: mydriasis
Cat: Salivation
Cat: blood pressure
Mouse: mydriasis
"For complete structures see Table 3.7.
*For complete structures see Table 3.7.
dR = (C6H5)2C(OH)C02CH2CH2-.

substance [i.e., CH3C02(CH2)2+N(CH3)3or stituents as blocking groups at the same car-

CH3(CH2),+N(CH3),] changes the compound bon atom (Table 3.11) but a third cyclic sub-
to an anticholinergic agent [ (C6H5)2CHC02(CHJ stituent lowers the anticholinergic activity
+N(CH3I3 and (C6H5)2CH(CH2),+N(CH,),, re- (193). When these cyclic groups are too large,
spectively]. such as biphenyl and naphthyl, the com-
Anticholinergics contain varied cyclic pounds have low anticholinergic activities. A
structures, the phenyl group being the most sufficiently large number of anticholinergics
common (65c). Very often one encounters cy- that contain only one cyclic group on carbon
clohexyl and cyclopentyl radicals and the cor- are known; however, there is usually also an
responding unsaturated groups (cyclohexenyl, aliphatic group or, even better, a hydroxyl
cyclopentenyl). Substances containing a-,or, group present in such a case. Examples of such
less frequently, P-thienyl radicals may possess compounds are the esters of tropic acid. The
high anticholinergic activity. Often un- introduction of a second benzene ring into the
branched (methyl, ethyl) or branched (isobu- a-carbon of tropic acid lowers the anticholin-
tyl, isoamyl) groups are located at the same ergic activity of its aminoalkyl esters ( 6 5 ~ ) .
carbon atom together with one or two cyclic It is difficult to assess which cyclic substitu-
groups. The anticholinergic activities of sub- ents contribute the most for the anticholin-
stances that contain only aliphatic radicals are ergic activity. It could be that the effect of one
lower than those of the corresponding co- or another moiety depends on the substituents
mounds with cyclic substituents. already present and on other characteristics of
The most common and, as a rule, the most the substance. An overwhelming majority of
active anticholinergics contain two cyclic sub- the therapeutically most active anticholin-
5 Structure-Activity Relationships

Table 3.11 Influence of Cyclic Radicals on Anticholinergic Activity

(Test System: Rabbit Intestine)

Name or Structure of Compounda Activity

Compound Ratio
Pair Series A Series B B/A Ref.
1 C6H5CH2R (C6H5),CHR 6.7 193
2 C6H5CH2R (C&J&R 0.7 193
3 CH2(OH)R C6H,CH(OH)R 23.3 193
4 C6H5CH(OH)R (CJ&)&(OH)R 114 193
5 Adiphenine (C6H5)CH(C6Hll)R 3.3 194,195
(transentine) (transentine-H)
6 Adiphenine Dicyclomine 10.0 196

ergics contain at least one phenyl group (Table

3.7). The second cyclic group, where there is
one, need not be a phenyl. It is even better if,
for example, it is a cyclohexyl, cyclopentyl, or
any other cyclic structure. Such unsyrnmetri-
cal doubly substituted compounds have higher
anticholinergic activities and lower toxicities
(65, 194, 195). This is a situation similar to
that in 5,5-disubstituted barbituric acid hyp-
notics and anticonvulsants.
A question might arise whether the aro-
matic (flat surface) nature of one of the cyclic
radicals is essential for anticholinergic activ-
ity, because such a large number of anticholin-
ergics contain a phenyl group. The sufficiently
high activity of compounds in which both sub-
stituents are alicyclic (e.g., cyclohexyl or cyclo-
pentyl) provides a basis for asserting that the H-C-H
aromatic nature of the substituents is not es- I
sential in anticholinergics (651365.
Not just the number and the character of
the cyclic group but also the mode of linking of
the substituents are important for anticholin-
ergic activity. Two benzene rings are linked The importance of the cyclic nature of the
differently in 2-diethylaminoethyl esters of di- substituent and not simply of its mass is evi-
phenylacetic acid (391, fluorene-9-carboxylic dent from the comparison of the anticholin-
acid (40) and p-biphenylacetic acid (41). Of ergic activities of 1-cyclohexyl-1-phenyl-3-pip-
these, the diphenylacetic acid derivatives have eridino-1-propanol (42) and 1-(n-hexy1)-1-
the highest anticholinergic activity (193). phenyl-3-piperdino-1-propanol (43), of which
(42) is an active anticholinergic, whereas (43)
is not effective (174).
As far as the contribution of cyclic struc-
tures to anticholinergic activity is concerned,
the introduction of cyclic groups into acetyl-
choline or a cholinergic compound leads to a
change in the pharmacological properties
that, without lowering and possibly even
Anticholinergic Drugs

ments for a chain of atoms that connects the

cationic head and the cyclic moieties; these ap-
ply to the length and form of the chain, lateral
branching, and functional groups in the chain,
if any.
A considerable number of the anticholin-
ergics belong to the group of aminoalkyl esters
of substituted acetic acids. In an overwhelm-
ing majority of cases, the substituted esters of
p-aminoethanol are more active as anticholin-
ergics than are the corresponding derivatives
of y-aminopropanol(119, 170, 175, 198). Fur-
ther increase of the chain length of the amino
alcohol leads to a decrease or disappearance of
the anticholinergic activity. The arninoalkyl
esters of diphenylacetic acid are more active
anticholinergics than the corresponding ami-
noalkyl esters of p,p-diphenylpropionic acid
(199). Therefore, in all these esters with high
anticholinergic activity the main chain con-
necting the cyclic moieties and the cationic
head contains five atoms (Table 3.12, series
1-3). In an homologous series of compounds in
which the ester group is replaced by a chain of
carbon atoms (Table 3.12, series 4-9), there
are three atoms in the main chain in com-
strengthening its affinity for the muscarinic
pounds with maximal anticholinergic activity.
receptor, abolishes or blocks the action of the
To explain the differences in the anticholin-
chemical transmitter. This phenomenon is
ergic activities of different series of com-
similar to the transition from a metabolite to
pounds, the ability of their structures to exist
an antimetabolite. It has been suggested that
in different spatial conformations has to be
the cyclic groups of the anticholinergic agent
taken into account.
form an additional contact with the musca-
Acetylcholine and related esters can exist
rinic receptor by hydrophobic or van der Walls
in two conformations (Fig. 3.5), the skewed
forces; as a result, this contact is strengthened
and extended forms (200) (e.g., 44 and 45, re-
and the muscarinic receptors are protected
spectively, for acetylcholine). The skewed
from approaching molecules of acetylcholine
form (44) of acetylcholine is closely related to
(174, 197). Cyclic groups of substantial size
the structure of muscarine (46) (200). Simi-
can create a kind of protective screen that
larly the substituted aminoethyl esters, which
sterically hinders the approach of molecules of
are anticholinergics, may exist in two confor-
acetylcholine, not only to the given active site
mations. The skewed forms of acetylcholine
but also to the vicinity of the active sites of the
(441, muscarine (461, the skewed form of ami-
receptor. Tricyclic anticholinergic agents may
noethyl esters (47), and the extended form of
fall under this category.
aminopropane derivatives (48) all interact at
the same muscarinic receptors. In the former
5.3 Length of the Main Chain Connecting
two compounds the interatomic distance be-
the Cationic Head and the Cyclic Croups
tween the quaternary nitrogen and the ether
The presence of the cationic head and of cyclic oxygen atom is nearly the same, and both of
groups is not sufficient for optimal anticholin- them are agonists. In (48) the interatomic dis-
ergic activity of a compound. The activity de- tance between the quaternary nitrogen and
pends on the mutual distribution of these the carbon atom to which the cyclic radicals
groups. This establishes the basic require are attached is the same, and both of them are
Table 3.12 Chain Length Between Cationic Head and Cyclic Radicals Among Anticholinergics
Value of n for High Total Number
Anticholinergic of Atoms in
No. Series Activity the Chain Test System Ref.
Rabbit: mydriasis 198

Rabbit: mydriasis 198

Mouse: mydriasis 119

Rabbit: ileum 158
Rabbit: ileum 158
Rabbit: ileum 158
Mouse: salivation
Mouse: salivation
Mouse: tremor
Mouse: salivation
"No exact values are available for esters with n = 1
Anticholinergic Drugs

Figure 3.5. Conformations of cholinergics and anticholinergics.

antagonists (65d)65. Thus, anticholinergic ac- ciently. A great importance was attached to
tivity depends not only on the length of the the complex
- esters in the initial period
- of the
main chain of the molecule but also on its abil- search for atropine-like substances, when ac-
ity to adopt a certain conformation that is fa- tive compounds were known only among the
vorable for the interaction of the substance esters of amino alcohols and carbowlic - acids.
with the receptor. However, the presence of this grouping is not
There is some information about the influ- necessary - for the manifestation of anticholin-
ence of branching of the main chain on the ergic activity. Presently, a large number of
anticholinergic activity. Esters with a methyl substances are known that belong- to different
group CY to the ester oxygen in the amino chemical structures and that possess high an-
alcohol part are less active than compounds ticholinergic activity (Table 7).
without the methyl group (175, 198, 201). The influence of an ester link can be as-
Similarly, the derivatives of 1,3-aminopropanol, sessed by comparing similar compounds that
aminopropane, and y-arninobutyronitrile (201, do not contain pharmacophoric groups other
203),which contain a branch at the carbon atom than the anchoring groups (amino nitrogen,
p to the nitrogen, are less active anticholinergics cyclic radicals). Comparative data on the
than the compounds without the branching. anticholinergic activities of the 2-diethyl-
The negative influence of such a side chain has aminoethyl ester of diphenylacetic acid
been explained by steric hindrance at the recep- [(C6H5),CHC0,CH,CH,N(C2H5)2] and 1,l-
tor (174). diphenyl-5-diethylaminopentane [(C6H5),-
The inclusion in the main chain of opti- CHCH,CH,CH,CH,N(C,H5),] indicate that
mum length of other atoms such as oxygen, they are equally active (65d). Thus, the com-
sulfur, nitrogen, and other functional groups plex ester group is not essential for anticholin-
changes any anticholinergic activity (65). ergic activity; however, it may contribute to
However, such compounds are considerably optimal activity when it is present in atropine-
potent (see Section 5.4). like compounds (123). It may influence the
conformation of a molecule that in turn deter-
5.4 Esteric Linkage
mines the effectiveness of the interaction of
The question of the importance of complex es- the essential anchoring groups, the cationic
ter grouping in anticholinergics, and even head and the cyclic radicals (65d), with the
more of its role, has not been cleared up suffi- muscarinic receptor.
5 Structure-Activity Relationships

5.5 Hydroxyl Croup tion decreases the original muscarinic activity

to about 113, whereas the introduction of both
The anticholinergic compounds that contain a a- and P-OH functions decreases the musca-
hydroxyl group in a certain position of a mol- rinic activitv" to about one-tenth.
ecule possess considerably higher activity The introduction of a hydroxyl group into
than similar compounds without the hydroxyl. 2-diethylaminoethyl phenylacetate approxi-
That position is of great importance. For es- mately doubles its activity (Table 3.13),
ters of amino alcohols and hydroxycarboxylic whereas the same structural change - in the
acids, maximum activity is achieved if the hy- corresponding ester of diphenylacetic acid in-
droxyl is p to the carboxyl group. Atropine is creases its activity about 140 times. The posi-
about 10 times more active than homatropine. tive influence of the hydroxyl group has been
However, esters with an a-hydroxyl also pos- observed in a large number of anticholinergics
sess considerable anticholinergic activity. In (Table 3.7). The exceptions are those cases in
anticholinergic amino alcohols the hydroxyl which the cyclic groups are too large or are
on the third carbon atom from the nitrogen connected in such a way that they can steri-
gives optimal activity (Table 3.7). The location cally prevent the interaction of the hydroxyl
of the hydroxyl group in relation to the cyclic with the surface of the muscarinic receptor.
radicals is also of vital importance. In the
great majority of anticholinergics they are lo- 5.6 Epoxy Group
cated at the same carbon atom or at adjacent
carbons. The presence of an epoxy group seems to in-
The hydroxyl group in anticholinergics can crease the mydriatic activity (Table 3.13).
be replaced by CN- and CONH,- groups However, scopolamine (7), which contains an
while preserving some degree of activity. How- epoxy group, is a central depressant, as indi-
ever, replacement of the hydroxyl by methoxy cated by drowsiness, euphoria, amnesia, and
or an acetoxy group lowers the activity (204, dreamless sleep. Atropine (4), which does not
205). contain an epoxy group, stimulates the me-
The hydroxyl group may interact by hydro- dulla and higher cerebral centers. In clinical
gen bonding with a site on the muscarinic re- doses (0.5-1.0 mg), this effect is usually con-
ceptor, which is rich in electrons. In support of fined to mild vagal excitation. Toxic doses of
this statement (65e), hydroxylated anticholin- atropine cause restlessness, disorientation, '

ergics form complexes in solution with sub- hallucinations, and delirium.

stances such as amines that contain electron-
donor atoms. In a series of structurally related 5.7 Stereoisomerism and Anticholinergic
compounds the anticholinergic activity was
proportional to their capacity for molecular
association by way of the hydroxyl group. 5.7.1 Opticalisomerism. Atropine (4-6) is
There is a direct relationship between the an- the racemic form of hyoscyamine, which is the
ticholinergic activity and the mobility of the (S)-(-)-tropyl ester of 3a-tropanol (2). The
hydrogen atom of the hydroxyl group as deter- carbon a to the carbonyl group is asymmetric.
mined by the rate of acetylation. The contri- (S)-(-)-Hyoscyamine is more active than (R)-
bution of the hydroxyl group to the free energy (+)-hyoscyamineas an anticholinergic (Table
of adsorption is quite high, of the order of 2 3.11). The alkaloid scopolamine (7) is the (S)-
kcal; it is apparently independent of the num- (-)-tropyl ester of scopine (8);again the (S)-
ber of methyl groups attached to the cationic (-) isomer is more active than (R)-(+) isomer
head (206). in its anticholinergic activities.
Although a hydroxyl group increases the A considerable number of synthetic anti-
activity of an anticholinergic, it does not con- cholinergic agents patterned after the struc-
vert a cholinergic substance into an anticho- ture of atropine contain an asymmetric carbon
linergic. Propionyl-, a-hydroxypropionyl-,and atom corresponding to the position of the
or$-dihydroxypropionylcholines possess cho- asymmetric carbon in atropine. In all com-
linergic properties (207). a-Hydroxy substitu- pounds examined, the asymmetric carbon is
Table 3.13 Muence of the Hydroxyl and Epoxy Groups on Anticholinergic Activity
Name or Structure of Compound
Group Series A Series B Test System B/A Ref.
Hydroxyl CJ-15CH2C02CH2N(C2H& C6H5CH(OH)C02CH2CH2N(C2H5)2 Rabbit: intestine 2.3 193
(C,H5)2CHC0,CH2CH2N(C2H5)2 (C6H5),C(OH)C02CH2CH2N(C2H5)2 Rabbit: intestine 143 193
Epoxy (- )-Hyoscyamine (-)-Scopolamine Guinea pig: ileum 0.24 208
Mouse: eye 2.70
Cat: eye 5.80
Cat: blood pressure 0.64
Cat: salivation 0.77
(-)-Methylhyoscamine (- )-Methylscopolamine Mouse: eye 1.00 208
Cat: eye 3.33
Cat: blood pressure 0.80
Cat: salivation 0.80
5 Structure-Activity Relationships 149

Table 3.14 Optical Isomerism and Anticholinergic Activity

Compounds Whose (+) Position of the
and (-1 Isomers Are Asymmetric Active Isomeric
No. Tested Test System Carbon Isomer Ratioa Ref.
Hyoscyamine Dog: salivation
Cat: salivation a-carbon to the
Cat: bloodpressure carbonyl
Guinea pig: ileum group
Rabbit: ileum
Scopolamine Dog: salivation a-carbon to the
Rabbit: intestine carbonyl
Tricyclamol Guinea pig: ileum Carbon with
cyclic radical
Benzhexol Guinea pig: ileum Carbon with
Rabbit: intestine cyclic radical
Mice: mydriasis
Procyclidine Guinea pig: ileum Carbon with
Mice: mydriasis cyclic radical
1,l-Diphenyl-3- Rabbit: intestine a to N
Methiodide of no. 6 Rabbit: intestine a to N

Diphenylacetate of 3- Rabbit: intestine p to N

"Activity ratio between the enantiomers.

located in the acyl moiety and is connected 3-quinuclidinyl diphenylacetate, the carbon
with the cyclic and the hydroxyl groups (di- atom p to the nitrogen is asymmetric; the (-)
rectly or through a methylene group). The (-1 isomer has more atropine-like activity than
isomers are often more active than (+) iso- does the (+) isomer.
mers (Table 3.14), indicating some apparent
stereospecificity with respect to the carbon 5.7.2 Derivatives of Tropine and Pseudo-
atom a to the carbonyl group of atropine. tropine. The configuration of the 3-OH group
The atropine-like activities of some com- in the tropine part of the molecule has signif-
pounds in which the asymmetric carbon atom icant influence on the activity at the musca-
is considerably closer to the amino group have rink receptor (Table 3.15). The derivatives of
been described. In 1,l-diphenyl-3-piperidino- +-tropine (pseudotropine, 3) are less active;
1-butanol, the carbon a to the nitrogen is +
the activity ratio for the compound relative
asymmetric. In this case the (+) isomer seems to the isomeric tropine varies from 2 to 13, but
to be more active than the (-) isomer. In more information is needed on this point.

Table 3.15 Relative Anticholinergic Activities of the Esters of Tropine and Pseudotropine

Pair of Structural Isomers Activity

Isomer Ratio
Pair A B Test System A/B Ref.
1 Atropine Tropyl-$-tropine Cat (?): blood pressure 2 213
2 Benzoyl-tropine HC1 Benzoyl-Jr-tropine Rabbit or Guinea pig: 3 214
3 CHJ of no. 2 CHJ of no. 2 Guinea pig: intestine 13 214
4 C,H,Br of no. 2 C,H,Br of no. 2 Guinea pig: intestine 4 214
Anticholinergic Drugs

5.7.3 Stereochemical Configuration. The constant of agonists (KA)and antagonists (K,)

acetylcholine-like cholinergics and atropine- acting at the same receptors, (2)the absolute
like anticholinergics contain similar pharma- configuration of the compounds, and (3) the
codynamic groups. In various hypotheses, it interrelationships between the configurations
has been assumed that both stimulant and of agonists and antagonists acting at the same
blocking drugs interact with the muscarinic receptors.
receptor through the essential pharmacody- The dissociation constants of some cholin-
namic groups. The tropic acid portion of atro- ergic agonists and antagonists have been de-
pine contains an asymmetric carbon, and the termined (Table 3.16). D(+)-and L(-)-lactoyl-
muscarinic receptor is stereospecific for the cholines are agonists at muscarinic receptors
carbon a to the carbonyl group in anticholin- and there is no significant difference in their
ergics. Acetylcholine does not contain such an intrinsic efficacies. The KAof D(+)-lactoylcho-
asymmetric carbon atom. Lactoylcholine is an line is lower than the KAof the L(-) isomer at
agonist that contains an asymmetric carbon the muscarinic receptor. Therefore, the D(+)
(2071, and the muscarinic receptor is ste- isomer has a higher affinity to the muscarinic
reospecific for the carbon a to the carbonyl receptor than that of the L(-) isomer (219).
group among lactoylcholine-like cholinergics Mandeloyl- and tropinoylcholines are compet-
(215). Because of the structural similarities in itive antagonists of acetylcholine and lactoyl-
tropic and lactic acids, it has even been sug- choline at the muscarinic receptors (220-222).
gested that a lactoylcholine-like parasympa- Among these anticholinergics, the D isomer
thetic neurohormone may occur in animal tis- has a higher affinity (l/K,) than that of the
sues (207, 216). However, this has not been corresponding L isomer. The above anticholin-
corroborated. ergics did not exhibit significant intrinsic effi-
cacies at the muscarinic receptors. The carbon
5.7.4 Dissociation Constants of Cholin- a to the carbonyl carbon of the ester group is
ergics and Anticholinergics. The absolute con- asymmetric in agonists (lactoylcholines) and
figuration [ ( R )and (S)] is self-consistent for a their competitive antagonists (mandeloylcho-
molecule in question and cannot be used to lines and tropinoylcholines). Therefore, the D
relate a series of compounds. The configura- isomers have the preferred relative configura-
tion in relation to a standard substance (D and tion that comes into definite spatial position
L) is very useful to compare a series of com- with the muscarinic receptor. Similarly, D(-)-
pounds. For example, the pharmacological pa- hyoscamine has a higher affinity to the mus-
rameters of all D compounds in a series can be carinic receptor than does the L(+)isomer and
compared with those of the L compounds, pro- has the preferred configuration (223).
vided each one of the compounds contains a
5.8 Compounds with Dual Action:
single asymmetric carbon (217).
Cholinergic and Anticholinergic Activities
In a number of studies on structure-activ-
ity relationships, the pharmacological activi- In several groups of atropine-like agents, de-
ties are expressed in terms of potencies or rel- rived from acetylcholine-like compounds, ago-
ative molar activities, which are derivatives of nist activity is replaced by partial agonist ac-
their ED,, values. The reciprocals of ED,, val- tivity and eventually antagonist activity with
ues do not give exact measures of affinities increasing substitution (224-227). For exam-
(218), which are required to make valid con- ple, a transition between cholinergic and anti-
clusions on the stereoisomer-receptor interac- cholinergic properties occurs when the acyl
tions and the nature of receptor surfaces. The group of acetylcholine is progressively length-
differences in the potencies of a pair of stereo- ened. Cholinergic activity decreases from
isomers may be attributed to the differences in formylcholine to butyrylcholine, and the
their affinities or intrinsic efficacies. For these higher members of the series are anticholin-
reasons, the following information is neces- ergics (Table 3.17). It has been demonstrated
sary to make definite conclusions for delineat- that hyoscyamine and atropine at small dose
ing receptor surfaces using stereoisomer-re- levels exhibit cholinergic properties (228,
ceptor interactions (217): (1)the dissociation 229).
6 Interaction of Anticholinergics at the Muscarinic Receptors

Table 3.16 Dissociation Constants and Intrinsic Efficacies of Cholinergic

and Anticholinergic Agents
Type of Dissociation Relative
Cholinergic or Anticholinergic ReceptoP Constantb Intrinsic
and Configuration (Test System) (KA or KB) Efficacy Ref.
Acetylcholine Muscarinic 1.08 X 1.00 219
Nicotinic 2.17 x 1.00 219
(R)-D-(+)-Lactoylcholine Muscarinic 7.3 x lo-5 0.52 219
Nicotinic 1.85 x 1.07 219
(S)-L-(-)-Lactoylcholine Muscarinic 3.02 X 0.30 219
Nicotinic 8.08 X 1.15 219
(R)-D-(-)-Acetyl-P-methylcholine Muscarinic Inactive - 224
(S)-L-(+)-Acetyl-P-methylcholine Muscarinic 1.24 X - 224
(active isomer)
(R)-D-(-)-Mandeloylcholine Muscarinic 3.00 X lop6 NSc 220,221
(S)-L-(+)-Mandeloylcholine Muscarinic 5.22 X NS 220,221
(S)-D-(-)-Tropinoylcholine Muscarinic 2.15 X lo-' NS 220,222
(R)-L-(+)-Tropinoylcholine Muscarinic 3.26 x NS 220,222
(S)-D-(-)-Hyoscyamine Muscarinic 4.47 X 10-lo NS 223
(R)-L-(+)-Hyoscyamine Muscarinic 1.41 X lo-' NS 223
"Muscarinic activities are tested on the guinea pig longitudinal ileal muscle in all cases except acetyl-p-methylcholine,
which is tested on the circular muscle from fundus of rabbit stomach. Nicotinic activities are tested on the frog rectus
abdominis muscle.
"Not significant.

6 INTERACTION OF ANTICHOLINERGICS line stimulates these receptors, atropine

AT THE MUSCARINK RECEPTORS blocks them. Although considerable progress
has been made in understanding these inter-
It is generally accepted that acetylcholine and actions of stimulant and blocking drugs, some
atropine interact with the same postgangli- aspects of drug-receptor interaction are not
onic muscarinic receptors. Whereas acetylcho- clear. For detailed discussions of cholinergic

Table 3.17 Cholinergic and Anticholinergic Activities of Choline Esters

a P& Test System Ref.
Rat: intestine 225
Rat: intestine
Rat: intestine
Rat: intestine
Rat: intestine
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Rat: intestine 225
Anticholinergic Drugs

and anticholinergic drugs at the muscarinic istence on the receptor of two active sites sep-
receptors see original papers and reviews on arated by a distance 3.2 + 0.2 A (219, 237-
the subject (230-236). 239). One of them is an anionic site with which
6.1 Kinetic Basis for the Mechanism of the quaternary ammonium group interacts to
Action of Anticholinergics induce stimulant or blocking actions. The
ether oxygen of muscarine and the ester oxy-
The major action of a number of anticholin- gen of acetylcholine interact with the second
ergics is a competitive antagonism to acetyl- site. There are some similarities between the
choline and other cholinergic agents. The an- active sites on acetylcholinesterase and the
tagonism can therefore be overcome by muscarinic receptor. The amine portion of an-
increasing the concentration of acetylcholine ticholinergics interacts at the same anionic
at receptor sites of the effector organs. Thus site as the quaternary group of acetylcholine
anticholinesterases partially reverse the an- and atropine. Several facets of acetylcholine-
tagonism of anticholinergics by sparing acetyl- atropine antagonism are well known:
choline at the receptor sites. The anticholin-
ergics can inhibit all muscarinic actions of 1. One molecule of atropine blocks one mole-
acetylcholine and other choline esters. Re- cule of acetylcholine. Atropine is a larger
sponses to postganglionic cholinergic nerve molecule than acetylcholine and either me-
stimulation may also be inhibited, but less chanically or electrostatically inactivates
readily than responses to administered cho- receptors engaged by it.
line esters. The differences in the ability of
2. Atropine has greater affinity than acetyl-
anticholinergics to block the effects of exoge-
choline for the receptor. Its intrinsic activ-
nous choline esters and the effects of endoge-
ity is not significant, whereas acetylcholine
nous acetylcholine liberated by the postgangli-
has high intrinsic activity. Substances with
onic parasympathetic nerves may result from
intermediate intrinsic activities behave ei-
the release of the chemical transmitter by the
ther as cholinergics or as anticholinergics,
nerve at the receptors in relatively inaccessi-
depending on the nature of their influence
ble sites where diffusion limits the concentra-
on the receptor. Among such substances
tion of the antagonist.
are partial agonists with "dual action";
6.2 Specificity of Antagonism cholinergic activity precedes the anticho-
linergic activity. The partial agonists can
Atropine is a highly selective antagonist of
be detected in a homologous series by grad-
acetylcholine, muscarine, and other cholin-
ually proceeding from agonists to antago-
ergic agents on the smooth and cardiac mus-
nists with increasing molecular weight.
cles and glands. This antagonism is so selec-
tive for cholinergic agents that atropine 3. Besides the cationic head, bulky cyclic
blockade of the actions of other types of drugs groups are essential constituents of com-
has been taken as evidence for their actions pounds with anticholinergic activity. It
through cholinergic mechanisms. For exam- seems clear that the van der Wads or hy-
ple, the smooth muscle of guinea pig ileum is drophobid binding of the planar cyclic
stimulated by muscarine, 5-hydroxytrypta- groups together with the binding of the
mine, histamine, and barium chloride. Atro- amine group produce a strong drug-recep-
pine is more specific in blocking the stimulant tor complex, which effectively blocks the
effects of muscarine and acetylcholine at lower close approach of acetylcholine to the
dose levels than those of the other three stim- receptor.
ulant agents. 4. Acetylcholine increases potassium efflux
and causes depolarization of the mem-
6.3 Molecular Basis for the Interaction of brane, both of which effects are blocked by
Acetylcholine and Anticholinergics at the atropine.
Muscarinic Receptors
5. The receptor proteins on the membrane
Structure-activity relationships among mus- may undergo molecular disorientation dur-
carinic agents (or cholinergics) indicate the ex- ing the interaction of acetylcholine with
7 Therapeutic Uses of Anticholinergics

Table 3.18 Mydriatic and Cycloplegic Activities of Anticholinergics in Man"

Mydriasis Cycloplegia
Strength of Maximal, Recovery, Maximal, Recovery,
D~gb Solution, % min days h days
1 Atropine sulfate 1.0 30-40 7-10 13 8-12
2 Owhenonium bromide 1.0 3040 7-10 13 8-12
3 Scopolamine hydrobromide 0.5 20-30 3-5 -12 -1 1-2
4 Atropine methyl nitrate 1.0-5 30 2 1 2
5 Homatropine bromide 1.0 1030 -4 - 4
1 1
1 1
-2 -2
6 Cyclopentolate 0.5-1.0 30-60 1 -21 -1 1
Dibutoline sulfate 5.0-7.5 60 1-
- -12 1 ---
1 1
4 2
8 Tropicamide c
1.0 20-35 -1
-12 2-6 h
9 Eucatropine hydrochloride 5-10 30 ---
1 1
4 2
None -
"For details see Refs. 241-243. The values should be considered approximate.
*Oneinstillation of one drop unless otherwise specified.
"Two drops at 5-min intervals.

the cholinergic receptor, and this change in The mydriatic and cycloplegic activities of
the receptor proteins may be prevented by anticholinergics in humans are listed in Table
a suitable blocking agent (240). Given that 3.18. Atropine is recommended in situations
five subtypes of muscarinic receptors have requiring complete and prolonged relaxation
been isolated and their amino acid se- of the sphincter of iris and the ciliary muscle.
quences have been determined, future in- Mydriatics, like cyclopentolate, eucatropine,
vestigations may reveal the molecular na- and homatropine bromide, with a shorter du-
ture of interactions of anticholinergics ration of action, are usually preferred for mea-
with muscarinic receptors. suring refractive errors because of the relative
rapidity with which their cycloplegic effects
7 THERAPEUTIC USES OF are terminated.
ANTlCHOLlNERGlCS Atropine and scopolamine are used for pre-
medication before the administration of some
The chief use of most of the antispasmodic inhalation anesthetics, to reduce excessive sal-
agents is as an adjunct in the management of ivary and bronchial secretions. Atropine and
the peptic ulcer; this group of drugs includes related agents have been used in the treat-
adiphenine, aminopentamide, amprotropine, ment of renal colic and hyperhidrosis, and to
dibutoline, diphemanil, glycopyrrolate, hexo- control sweating that may aggravate certain
cyclium, homoatropine methylbromide, meth- dermatologic disorders. Atropine also may be
scopolamine bromide, methscopolamine nitrate, used to counteract the toxicity of certain cho-
oxphencyclimine, oxphenonium, penthienate, linergic drugs and anticholinesterase agents.
pipenzolate, piperidolate, pipethonate, propan- Certain drugs with anticholinergic effects
thelin, tricyclamol, and trihexethyl (241). To are used for the symptomatic treatment of
this group of several M1 receptor antagonists Parkinson's disease (paralysis agitans) and re-
that decrease acid secretion should be added lated syndromes of the extrapyramidal tracts.
pyrenzipine, which is a leading compound in this (Of the presently available drugs, none is use-
group of agents. The anticholinergic agents that ful in all cases of Parkinsonism.) Despite
are useful as adjuvants in the management of claims of superiority for newly introduced syn-
the functional disorders of the bowel (e.g., irri- thetic agents, none possesses outstanding effi-
table colon, spastic colitis, ulcerative colitis, and cacy and freedom from adverse side effects
diverticulitis) include dicyclomine, hexocyclium, when compared clinically with atropine and
mepenzolate, and valethamate. scopolamine (241).
Anticholinergic Drugs

8 MOLECULAR BASIS FOR THE SIDE of euphoria, dizziness, and delirium may be
EFFECTS OF ANTlCHOLlNERClCS observed because the drugs can cross the
blood-brain barrier.
The most widely used mode of approach in the Many synthetic quaternary ammonium
design of anticholinergics is based on the use compounds may block acetylcholine at ganglia
of tropine alkaloids as models of prototypes, at high doses. Ganglionic-blocking agents
from which congeners or homologs or analogs cause impotence as a side effect. High doses of
have been designed. Tropine alkaloids have methantheline may also cause impotence, an
many pharmacological activities and interact effect rarely produced by pure antimuscarinic
at many cholinergic sites. In drug design the drugs and indicating ganglionic blockade.
main purpose is to increase one pharmacolog- Toxic doses of quaternary ammonium com-
pounds (e.g., menthantheline, propantheline,
ical action at one particular site of action while
and oxyphenonium) block acetylcholine at the
concomitantly suppressing other pharmaco-
somatic neuromuscular junction and paralyze
logical activities at other sites. It is not always respiration.
possible to abolish all pharmacological effects Adiphenine and amprotropine have local
other than the desired activity by molecular anesthetic activities, and anesthesia of the
modification. Though the desired activity is oral mucosa results when tablets of these
useful in its therapeutic applications, other drugs are chewed. It should be remembered
pharmacological activities manifest them- that local anesthetic esters and amides exert
selves as side effects. For example, atropine, their action by anticholinergic mechanisms,
scopolamine, and cocaine are structurally re- probably essentially at the nodes of Ranvier.
lated, each having atropine nucleus. They dif- The central side effects have appeared
fer in some of their pharmacological activities. among children even when cyclopentolate,
Atropine stimulates the CNS, scopolamine de- tropicamide, and other anticholinergics are
presses the CNS, and cocaine is a local anes- used as mydriatics. All anticholinergics in-
thetic and CNS stimulant. crease intraocular pressure in most patients
By molecular modification, it has been pos- with simple glaucoma.
sible to produce a series of anticholinergics Some of the cyclic groups in anticholin-
having qualitative effects resembling those ergics are pharmacophoric moieties for other
produced by parasympathectomy to a particu- types of activities. For example, the com-
lar organ. Although these drugs exert specific pounds containing a phenothiazine nucleus
therapeutic effects at one organ, they exert exhibit central depressing and antihistaminic
side effects at other organs. Recent develop- side effects. These side effects are of advan-
ments on the design of anticholinergics selec- tage in the treatment of Parkinson's syn-
tive for subtypes of muscarinic receptors and drome. The side effects of certain drugs that
identification of subtypes of muscarinic recep- result from their anticholinergic activities are
tors in a number of organs has partially pro- prominent among some analgesics (e.g., me-
vided a solution for this problem. peridine), antihistamines (e.g., prometha-
The untoward effects associated with the zine), psychosedatives (e.g., benactizine), and
use of anticholinergics are manifestations of psychotomimetics (e.g., dexoxodrol).
their pharmacological actions, and usually oc-
cur on excessive dosage. The effects include 9 PROFILE O F ANTlCHOLlNERClC
dryness of mouth, blurred vision, difficulty in ACTIVITIES OF VARIOUS AGENTS
urination, increased intraocular tension,
tachycardia, and constipation. Most of these The relative anticholinergic activities of the
side effects are lessened when the quaternary well-known therapeutic compounds are listed
anticholinergics are administered orally in the in Table 3.19. Although it is very difficult to
treatment of peptic ulcer because of low ab- justify collecting the results of a wide variety
sorption into the systemic circulation. In the of experiments, it seems likely that the table
case of tertiary amines the central side effects gives some idea of their relative antisecretory,
10 Nonanticholinergics as Antiulcer Agents 155

antispasmodic, and mydriatic activities rela- Studies on the effectiveness of anticholin-

tive to atropine. Ratios less than unity indi- ergic agents in the ulcer disease complicated
cate that they are more active than atropine. by Helicobacter pylori infection are hampered
Atropine itself is a very active substance in by the lack of suitable animal models (262).
all three types of activities. (-)-Methscopol- Marchetti et al(263) have developed a mouse
arnine seems to be the most active of all com- model of H. pylori infection that mimics hu-
pounds; it is about five times as active as atro- man disease. The pathogenesis of H. pylori in-
pine. None of the synthetic compounds is more fection in vivo was investigated using fresh
active than (-)-methscopolamine, and very clinical isolates of bacteria to colonize the
few of them are more active than atropine. stomachs of mice. The gastric pathology re-
The compounds with high antisecretory activ- sembling human disease was observed with
ities also exhibit some degree of antispasmodic cytotoxin-producingstrains but not with non-
and mydriatic activities. Therefore, there is no cytotoxin strains. Oral immunization with pu-
complete dissociation between the three types rified H. pylori antigens protected mice from
of anticholinergic activities. Compounds with bacterial infection. This model will be useful
only one type of anticholinergic activity have for the development of therapeutic regimens
yet to be synthesized. Only among very weak involving vaccines against H. pylori and anti-
compounds is there any dissociation between cholinergic agents.
the antispasmodic and the mydriatic activities
(e.g., propivane). However, this difference
may be related to the mode of administration. 10 NONANTICHOLINERGICS AS
Mydriatic activities are measured after instil- ANTIULCER AGENTS
lation into the eye, whereas antispasmodic
and antisecretory activities are measured af- The interplay of various neuronal, hormonal,
ter parenteral administration to the animal or and other factors in gastric acid secretion are
on in vitro preparations. To establish a claim shown in Fig. 3.1. Pharmacological agents can
that one compound has only one type of anti- be used to decrease gastric acid secretion by
cholinergic activity, two types of data should their action at different sites. So far, the prin-
be available: (1)all types of activities should be cipal medications other than anticholinergics
measured in the same animal after the drug is and antiacids to treat peptic ulcer are limited.
Experimental and clinical investigations are
administered by the same route; (2) the exact
in progress on a number of agents that can
concentrations of the drugs at the sites of their
decrease the volume and acidity of gastric
action should be known. Such information is secretion through mechanisms other than
not available for most compounds in published blockade of the cholinergic nervous system
literature. (264-267). These include (1) histamine H2-
For their antispasmodic and antisecretory receptor antagonists (2661, (2) gastrin inhibi-
activities in humans, the drugs are adminis- tors (265), (3) pepsin inactivators (2651, (4)
tered orally. A comparison of their oral doses mucus producers (69), (5)prostaglandin ana-
(micromoles) indicates that atropine is the - (69). (6) enteromstone
logs - and its analogs-
most active compound. In clinical experience (265, 267), (7) noncholinergic antispasmodics
all three types of anticholinergic activities are (69, 264), and (8) gastric Hf/Kt-ATPase in-
exhibited by all compounds. The principal ad- hibitors.
vantage of the available quaternary ammo- Histamine HZ receptor antagonists are
nium compounds lies in the fact that they are popular for the treatment of peptic ulcer (266).
elatively free of any of the CNS effects that A single dose of cimitidine, an HZ receptor an-
may be seen with atropine. This may permit tagonist, has a maximum effect on nocturnal
the administration of sufficient quantities of acid output in humans, and no further effect is
the compounds to achieve a more fully effec- obtained by adding poldine, an anticholinergic
tive peripheral anticholinergic action. agent, to cimitidine (266~).Cimitidine is also
Table 3.19 Relative Activities of Anticholinereicsa
Total Dose Per Day in
Equipotent Molar Ratios Relative to Atropine Humans f

No. Antisecretoryd Antispasmodice Mydriatic mg pmol Ref.

Solanaceous Alkaloids and Semisynthetic Substitutes
Atropine sulfate

Synthetic Anticholinergics: Esters, Quaternary


Poldine methyl sulfate
Esters, Tertiary
Amprotropine phosphate

Thioesters, Tertiary
Triphenamil 6.0rb

Carbamates, Quaternary
Dibutoline sulfate

Main Chain: Alkane, Quaternary

Hexocyclium methyl
Isopropamide iodide 0.85rb
Mepiperphenidol 0.48g
Tricyclamol chloride 1.2g 2.3m
Trihexethyl chloride 2.17rb
Main Chain: Alkane, Tertiary
Aminopentamide 2.lrb
Benzhexol 3.7g 16m
Procyclidine 2% 31m

Main Chain: Alkene, Quaternary

Diphemanil methyl 8.0g
"No comparative studies of all anticholinergics in the same animal species or on the same test system are available. The above data were assembled or cross-calculated from
information reported in a number of sources; therefore the activities are relative and approximate. However, the information is useful to compare the available anticholinergic agents.
bAll quaternary salts are bromides, and all tertiary m i n e s are listed as hydrochlorides unless otherwise specified.
'The compounds were tested in different species. The following abbreviations are used to indicate the species: c, cat; d, dog; h, human; g, guinea pig; m, mouse; r, rat; rb, rabbit.
Values less than unity indicate that they are more active than atropine.
dAntisecretory activities are on salivation unless otherwise indicated. "a" after the species indicates inhibition of acid secretion.
'All antispasmodic activities are inhibition of the contraction of intestine using cholinomimetic as spasmogen.
fThe total dose includes the initial dose, as well as maintenance dose used orally (except dibutoline, which is administered subcutaneously) in man.
Anticholinergic Drugs

an effective drug in healing gastric and duode- 11 ANTICHOLINERGICS DEVELOPED FOR

nal ulcers. Anticholinergic drugs and antacids SPECIFIC USES
help to control symptoms, but they do not ac-
celerate healing. Promethazine, an antihista- Ipratropium (Atrovent) was first developed
minic inhibits the release of gastrin in the dog for the symptomatic treatment of obstructive
and humans (265). (bronchospastic) disease (268). It is a deriva-
Pepsin inhibitors, sulfated amylopectin tive of atropine. Two chemical features distin-
(Depepsin),and carrageenin decrease acid se- guish it from atropine: ( I ) an isopropyl group
cretion in experimental animals and protect replaces the N-methyl group of the atropine
animals against histamine-induced ulcers component; (2)the methyl quaternary group
(265). They have to be studied further ade- (as the second substituent on the N-atom)
points toward the pyrrolidine part of the ring
quately to ascertain their therapeutic useful-
system and occupies an equatorial position.
These structural features allow the Ipra-
Carbenoxolone and cimetidine are comple- tropium molecule to attain a relatively selec-
mentary in their contribution to the healing of tive bronchodilator effect on the cholinergi-
peptic ulcers, and the use of both may be bet- cally innervated airways. By the inhalation
ter than either singly for some patients. Car- route of application, this poorly absorbable
benoxolone accelerates healing by helping the quaternary ammonium derivative becomes se-
defense mechanisms of the body. It stimulates lective to primarily affect the airway smooth
extramucus secretion and prolongs cell life in muscle. Another advantage of ipratropium
the gastric epithelium. Cimetidine reduces over atropine is that, in contract to the latter,
gastric acid secretion. It would be interesting it does not suppress mucociliary function.
to know whether anticholinergic drugs are A novel series of N,N1-disubstituted6,7-di-
more effective for the treatment of peptic ul- azabicyclo-(3,2,2)-nonane derivatives were
cer in the presence of carbenoxolone. synthesized and pharmacologically tested
Carbenoxolone (Biogastrone, Duogas- (268). Compounds belonging to the 3-(uconfig-
trone) is the disodium salt of glycyrrhetinic uration were more potent than those of the
acid hemisuccinate. It is prepared by hydroly- 3-P configuration. The quaternary ammonium
sis of glycyrrhizic acid, a glycoside in licorice derivatives were also more potent than the
root. It increases the secretion of mucus and tertiary amines in this series. Ba 679 Br,
accelerates the healing of gastric ulcers. This tiotropium bromide, a new azoniatricyclo non-
drug is now under clinical investigation in the are derivative has shown potent bronchodila-
United States. tor activity that significantly outlasts that of
ipratropium (269-271). This special feature
Pharmacological doses of several prosta-
and its selectivity can be explained by its
glandins and their analongs inhibit gastric
slower dissociation rate from M1 and M3 than
acid secretion. 15-(R)-Methyl-PGE,, in small
from M2 muscarinic receptors. In patients
doses (100-200 pg, oral), reduces gastric acid with chronic obstructive pulmonary disease
secretion and output in humans and animals, (COPD) tiotropium is significantly more effec-
and it is currently being studied in the treat- tive than ipratropium. Several studies indi-
ment of peptic ulcer. cate that tiotropium is very useful for long-
Among the nonanticholinergic antispas- term maintenance treatment of patients with
modics, alverine citrate (Spacolin) and iso- airflow obstruction resulting from COPD.
metheptene (octin) hydrocholoride or mu-
cate are available on the market. They relax
smooth muscle by nonspecific actions. They 12 ACKNOWLEDGMENTS
exert little effect on gastric acid secretion.
They are most useful in the symptomatic The author is supported by USHHS-NIH Re-
treatment of gastrointestinal disorders char- search Grant DA-06207; The Council for To-
acterized by hypermotility and spasm. bacco Research, USA, Inc.; The Smokeless To-

bacco Research Council, Inc.;and The Center 19. D. D. Bonnycastle in D. R. Laurence and A. L.
for Anaesthesia Toxicology of Vanderbilt Uni- Bacharach, Eds., Evaluation of Drug Activi-
versity. ties: Pharmacometrics, Vol. 2, Academic, New
York, 1964, pp. 507-520.
20. E. G. Vernier in D. R. Laurence and A. L. Ba-
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CNS Stimulants
Department of Medicinal Chemistry and
Molecular Pharmacology
School of Pharmacy and Pharmacal Sciences
Purdue University
West Lafayette, Indiana

1 Introduction, 168
1.1 Ephedra and Khat, 168
1.2 Caffeine, 169
2 History, 172
3 Clinical Use of Agents, 172
3.1 Therapeutic Applications, 172
3.1.1 Attention Deficit Hyperactivity
Disorder (ADHD), 172
3.1.2 Narcolepsy, 173
3.1.3 Use for Depression in Terminal Illness,
3.1.4 Use in Obesity, 173
3.1.5 Apnea in Premature Infants, 173
3.2 Side Effects, Adverse Effects,
and Drug Interactions, 174
3.2.1 Methylphenidate, 174
3.2.2 Pemoline, 174
3.2.3 Cocaine, 175
3.2.4 Caffeine, 176
3.3 Absorption, Distribution, Metabolism, and
Elimination, 176
3.3.1 Amphetamine Metabolism, 176
3.3.2 Methylphenidate Metabolism, 177
3.3.3 Cocaine Metabolism, 177
3.3.4 Diethylpropion Metabolism, 177
4 Physiology and Pharmacology, 179
4.1 Where and How These Drugs Work, 179
4.2 Biochemical Pharmacology: Receptor Types
and Actions, 180
4.2.1 A Role for Serotonin, 182
4.2.2 A Role for Norepinephrine, 183
5 Structure-Activity Relationships, 184
5.1 Amphetamine, 184
Burger's Medicinal Chemistry and Drug Discovery 5.1.1 Length of the Side-Chain, 185
Sixth Edition, Volume 6: Nervous System Agents 5.1.2 Nitrogen Substituents, 185
Edited by Donald J . Abraham 5.1.3 Stereochemistry a t the a! Carbon, 186
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 5.1.4 The a!-alkyl Substituent, 186
CNS Stimulants

5.1.5 Other Side-Chain Substitutions, 186 5.3.5 Substitutions on the Aromatic Ring at
5.1.6 Aromatic Ring Substitution, 187 Position 3, 191
5.2 Methylphenidate, 187 5.3.6 Requirement for the Intact Tropane
5.3 Cocaine, 188 Ring System, 192
5.3.1 N-substituents, 188 6 Recent and Future Developments, 192
5.3.2 Basic Nitrogen Atom, 189 6.1 Web Site Addresses and Recommended
5.3.3 Substituent at C(2),189 Reading, 194
5.3.4 The Ester Linkage at C(3),191

1 INTRODUCTION prescribed for appetite control, but they lose

efficacy rather quickly through the develop-
Natural products that have stimulant proper- ment of tolerance. Thus, it was not uncommon
ties have been known for millennia, and their for patients to become dependent on them,
active species (including ephedrine and co- with symptoms of withdrawal upon abrupt
caine) are now well known. Stimulants, also cessation. The increased awareness of the ad-
called psychostimulants, are drugs that lead to dictive potential of stimulants, coupled with
increased arousal, improved performance on their widespread abuse, has led to much more
tasks of vigilance and alertness, and a sense of extensive restrictions over their availability.
self-confidence and well-being. High doses can These drugs are much more carefully con-
produce feelings of elation or euphoria. Be- trolled today, and are rarely used for weight
cause of their ability to produce elation and control except in a few special instances.
euphoria, the stimulants have reinforcing There remain some important medical uses
properties and can lead to dependency. That for this class of drug, yet as noted later, the
is, because they make users feel "good," they therapeutic actions of psychostimulants must
are sometimes taken for extended periods of be balanced against their undesirable actions.
time in an attempt to maintain an elevated Issues of dependency, tolerance, and potential
mood. abuse must be considered when deciding
Tolerance develops to the mood-elevating whether treatment with a psychostimulant is
properties of psychostimulants, however, and an appropriate therapy. On the other hand,
more and more of the drug must be taken to new generations of drugs that have sprung
maintain the effect. Increased doses also pre- from an understanding of the classic stimu-
vent sleep, and continued use can result in lants may open important therapeutic hori-
symptoms of psychosis. Cessation of the drug zons for the future. Table 4.1 catalogs various
after one of these binges may lead to an emo- data on psychostimulant and anorexigenic
tional and physical "crash" (the result of poor preparations.
nutrition, lack of sleep, and increased physical
activity), and severely depressed mood. In de-
1.1 Ephedra and Khat
pendent individuals, craving for the drug oc-
curs, resulting in another period of extensive The Chinese drug ma huang (Ephedra sinica
drug use with the subsequent crash. This cycle Stapf) has been used in China for more than
is repeated in chronic psychostimulant depen- 5000 years. The alkaloid that is responsible for
dency. the CNS stimulant effects is ephedrine. The
Many central nervous system (CNS) stim- levorotatory erythro isomer (1)is the most ac-
ulants also have appetite-suppressant effects tive of the four possible stereoisomers with
that led to their use in treating obesity. In that structural formula. Khat (kat, or qat) or
short-term studies, amphetamine-like drugs Abyssinian tea (Catha edulis Forskal) is the
have been shown to be more effective than product from a small tree or shrub indigenous
placebo in promoting weight loss. Long-term to tropical East Africa. Khat leaves are chewed
(>20 weeks) weight loss has not been shown, habitually by peoples in East Africa and cer-
however, unless the drug is taken continu- tain other Arabian countries, and produce a
ously (1).At one time, stimulants were widely mild CNS stimulant effect (2). The principal
1 Introduction

active component in Khat is a substituted where it occurs to the extent of about 3.5%, by
phenethylamine derivative known as (-)- weight), of coffee beans (Coffea arabica, where
cathinone (2) (3). it constitutes about 1-2% by weight), and tea
(Camellia sinesis, where it makes up 1-4% of
the mass of dried leaves). The annual con-
sumption of caffeine has been estimated at
120 million kilograms, the approximate equiv-
alent of one caffeine-containing beverage per
day for each of the world's six billion plus in-
habitants. As a beverage, the worldwide con-
sumption of tea is surpassed only by water.
The structurally related dimethylxanthines,
theophylline (5) and theobromine (61, have
less of a CNS stimulant effect, and are princi-
pally important for their ability to relax
smooth muscle. Cocoa and chocolate have lit-
tle caffeine, but do contain theobromine.

Both of these compounds possess a p-phen-

ethylamine framework, a common structural
theme that occurs in many related CNS stim-
ulants. In general, these compounds have sim-
ilar mechanisms of action.
(-)-Cocaine (3) has a completely different
structure and, as we shall see later, its mech-
anism of action is also somewhat different
from the structurally simpler (1)and (2). Nev-
ertheless, all of these natural prototype CNS
stimulants have the common action of exert-
ing powerful effects on brain pathways that
utilize dopamine as the neurotransmitter.

1.2 Caffeine
From an economic standpoint, the most im-
portant CNS stimulant is caffeine (1,3,7-tri- A regular cup of coffee contains between 40
methylxanthine, 4). It occurs naturally and is and 176 mgof caffeine, with a mean content of
a product of kola (cola) nuts (Cola nitida, about 85 mg. Tea contains less caffeine, with
Table 4.1 Psychostimulant and Anorexigenic Preparations
Generic Name Dosea
(structure) Trade Name Originator Chemical Class (mgtday)
Cocaine HCl(3) Cocaine HCl powder Mallinckrodt Ecgonine methyl ester NA
Amphetamine (7) Adderall Shire Richwood Phenethylamine 5-30 mg
Amphetamine Amphetamine sulfate Lannett 5 mg
sulfate (7)
Dextroamphetamine Dextroamphetamine sulfate Various 5-10 mg
sulfate (10)
Dexedrine SmithKline-Beecham
0 Richwood
Methamphetamine Desoxyn Abbott 5 mg
Desoxyn Gradumet Abbott 5-10 mg
Methylphenidate Methylphenidate HC1 Various a-Phenyl-2-piperidineacetic 5-20 mg
HCl(8) acid methyl ester
Ritalin Ciba-Geigy
Methylin Mallinckrodt
Metadate ER Medeva 10 mg, ER
Concerta Alza 18 mg, ER
Modafinil(44) Provigil Cephalon Diphenylmethyl-sulfinyl-2- 100-200 mg
Pemoline (9) Pemoline 2-Amino-5-phenyl- 18.75-75 mg
Cylert Abbott
PemADD Mallinckrodt
Caffeine (4) Quick Pep; Caffedrine; NoDoz; Thompson; Thompson; Bristol-Myers; Trimethylxanthine 75-200 mg
Stay Awake; Vivarin; Stay Major; SK-Beecham; Apothecary;
Alert; Enerjets; Starbucks Chilton
Benzphetamine (22) Didrex Upjohn Phenethylamine 25-50 mg
Diethylpropion (16) Diethylpropion various Phenethylamine 25-75 mg
Tenuate Aventis Phenethylamine
Phendimetrazine Phendimetrazine various Phenethylamine 35 mg
Bontril PDM Carnrick
Plegine Wyeth-Ayerst
Phendimetrazine various 105 mg, SR
Adipost Jones
Bontril Slow-Release Carnrick
Dital UAD
Dyrexan-OD Trimen
Melfiat-105 Unicelles Numark
Prelu-2 Boehringer-Ingelheim
Rexigen Forte ION Labs
Phentermine (19) Phentermine Various Phenethylamine
Ionamin Medeva
-.L Fastin SmithKline-Beecham
V Ion
d zantqd
Adipex-P Lemmon
Obe-Nix 30-P Holloway
Decongestants and
Ephedrine sulfate Pretz-D 0.25% spray Parnell Phenethylamine NA
Ephedrine sulfate West-Ward Phenethylamine 25 mg
Ephedrine sulfate Various Phenethylamine 50 mg/mL
aAdministered orally unless otherwise noted.
CNS Stimulants

an average of about 27 mg per cup, and an narcolepsy (7) and, by 1936, orally active
ounce of sweet chocolate typically contains be- Benzedrine tablets were available without
tween 75 and 150 mg of combined methylxan- prescription (8). By 1937 it was being used
thines (4). recreationally by the general population,
The reader should be aware that the use of with particular popularity among American
the term CNS stimulation encompasses sev- college students (9).
eral physiological mechanisms of action and It is not clear when or by whom metham-
many different types of biologically active phetamine was first synthesized. Various ac-
substances. A number of different agents, in- counts indicate its first preparation some-
cluding caffeine (see below), affect these phar- where between 1888 and 1934 (5). In any case,
macological mechanisms and cause CNS stim- Hauschild (10) published the first studies of
ulation. Other diverse examples include the pharmacology of methamphetamine in
strychnine (causing CNS stimulation by 1938, characterized its stimulant effects in an-
blockade of inhibitory glycine receptors) and imals, and also carried out a self-experiment.
benzodiazepine inverse agonists (causing CNS
stimulation by decreasing the inhibitory ef-
fects of GABA on inhibitory chloride chan-
nels). It is not the intent of this chapter to
3.1 Therapeutic Applications
provide an encyclopedic treatment of all the
possible substances that can cause "CNS stim- Psychostimulants generally increase the level
ulation," but rather to focus primarily on the of activity, alleviate fatigue, increase alert-
psychostimulants (i.e., drugs that affect brain ness, and elevate mood (or cause euphoria in
monoaminergic systems). high doses). Unfortunately, the ability to pro-
duce euphoria leads these compounds to have
a high potential for abuse and dependency.
2 HISTORY The principal clinical indications for psycho-
stimulants are in the treatment of attention
The historical development of amphetamine deficit hyperactivity disorder (ADHD) and the
and methamphetamine is described in inter- sleep disorder known as narcolepsy. A less
esting detail by Angrist and Sudilovsky (5). commonly recognized use, but one that' is
The discovery of psychostimulants differs gaining importance, is in the treatment of de-
somewhat from the usual drug discovery pro- pression in terminal patients or the chroni-
cess because there was a long folkloric history cally ill (11-13). There is also need for psycho-
of the use of khat, coca leaves, and ma huang stimulants in certain occupations (e.g., in the
(ephedra). Although there may not have been military), as a countermeasure to fatigue from
a formal pharmacologicalclassification of CNS irregular or prolonged work hours, where a
stimulants at that time, the ability " of these high level of vigilance and alertness must be
agents to alleviate fatigue was well recog- maintained (14, 15). Some specific clinical ap-
nized. plications include the following.
Amphetamine itself was synthesized in
1887 and first studied as early as 1910, but its 3.1 .I Attention Deficit Hyperactivity Disor-
stimulant effects were not discovered until der (ADHD). ADHD is a diagnosis applied
about 1930. Amphetamine was independently mostly to children, but one that persists into
resynthesized in 1927 by the noted psycho- adulthood for many people. It is reflected in a
pharmacologist Gordon Alles in a program to persistent pattern of inattention and/or hy-
develop synthetic substitutes for ephedrine, a peractivity-impulsivity that is more frequent
drug then being used as a bronchodilator for and severe than typically observed in individ-
the treatment of asthma (6).
. . The central stim- uals at a comparable level of development (16).
ulant effects of amphetamine were probably Inattention prevents ADHD patients from
noted about 1930, when it appeared in nasal keeping their mind on one thing and focusing
inhalers in Germany. The first medical use their attention; they are easily bored with a
for amphetamine was in the treatment of task after only a short while. They have no
3 Clinical Use of Agents

difficulty devoting attention to activities that that may occur without warning and are often
they enjoy, but find it hard to focus conscious irresistible. Another hallmark symptom of
attention to organizing or completing a task, narcolepsy is cataplexy, which is a sudden loss
or learning something new. They may forget of voluntary muscle control, often triggered by
to plan ahead and tasks are rarely completed, emotions such as laughter or surprise. Cata-
or are filled with errors. plexy occurs more frequently during stress or
Children with ADHD (particularly of fatigue. The attack may involve only a feeling
school age) have great difficulty being still, of weakness and limp muscles or it may result
they may be in and out of their seats, and talk in total muscular collapse, during which the
incessantly. The inability to focus makes person can appear unconscious, but actually
learning tasks boring, and exacerbates the de- remains awake and alert. Attacks may be very
sire to move around and become involved in brief or may last for tens of minutes. Another
distractions. ADHD children may squirm, characteristic symptom of narcolepsy is hyp-
shake their legs, touch everything, or make nagogic hallucinations. These are vivid, realis-
distracting noises. Hyperactive teens and tic, and often frightening, reminiscent of
adults may feel intensely restless, and may try nightmares, and are usually accompanied by
to do several things at once, going from one sleep paralysis, a temporary inability to move.
activity to the next. Impulsivity is another Whereas the psychostimulants can have a
characteristic of ADHD, with patients often beneficial effect, they are likely to be sup-
acting without thinking about the conse- planted by newer drugs that are more specific
quences. They may have difficulty curbing and have fewer side effects.
their immediate reactions to situations, mak-
ing inappropriate remarks without thinking 3.1.3 Use for Depression in Terminal 111-
what they are saying. They find it hard to wait ness. Although this indication for psycho-
for things they want or to wait to take their stimulants is not as widely recognized, agents
turn. such as amphetamine and methylphenidate
In normal subjects, psychostimulants can are preferred because they do not suffer from
increase activity and talkativeness, especially the weeks-long delay in onset of action that is
at higher doses. Paradoxically, in ADHD suf- characteristic of traditional antidepressant
ferers, stimulants appear to have a calming medications. Thus, a rapid antidepressant re-
effect, and allow an increased focus and atten- sponse can be achieved in severely ill patients,
tion to tasks. Although appearing paradoxical, who in some cases may not survive long
it is now believed that the decreases in activity enough for a traditional antidepressant medi-
in ADHD are secondary to improvements in cation to begin to have an effect (11, 17-19).
attention. This beneficial effect of low doses of
the stimulants has led to a large number of 3.1.4 Use in Obesity. As noted earlier,
children being prescribed methylphenidate many of the psychostimulants have also been
(Ritalin) or various amphetamine prepara- used as anorectics (anorexics; anorexigenics),
tions for the treatment of ADHD. This, in that is, as appetite suppressants. A few of
turn, led to great concern about the fact that them are still useful in this regard, but the
these drugs were overprescribed for ADHD, high abuse potential of psychostimulants, cou-
and that children who are merely highly ener- pled with the development of tolerance to
getic were routinely being given them for be- their anorectic effects, has meant that pre-
havior management. The reader should be scribing psychostimulants for weight control
aware of this social issue, but it requires no has generally fallen into disfavor.
further comment in the context of this chap-
ter. 3.1.5 Apnea in Premature Infants. Apnea of
prematurity (AOP) occurs in about 90% of
3.1.2 Narcolepsy. Narcolepsy is a condi- premature neonates weighing less than 1 kg
tion that includes as its predominant symp- at birth, and in 25% of infants with a weight of
tom, excessive daytime sleepiness (EDS), per- less than 2.5 kg (20). The first-line pharmaco-
sistent drowsiness, and daytime sleep attacks logical therapies for the management of AOP,
CNS Stimulants

to stimulate respiration, are the methylxan- been recently discussed extensively by Angrist
thines, with theophylline (5) presently being (27). Interestingly, psychostimulants can in-
most extensively used. Recent studies suggest, duce a psychotogenic response in schizophren-
however, that caffeine (4) should be consid- ics, in doses that are subpsychotogenic in nor-
ered the drug of choice because of similar effi- mal subjects, and methylphenidate was found
cacy, longer half-life, fewer adverse effects, to have greater potency in this regard (28).
and better brain penetration than that of the- Activation of psychotic symptoms by methyl-
ophylline (21). phenidate was found to be a predictor of risk of
relapse (29). These, and other studies, are all
3.2 Side Effects, Adverse Effects, consistent with the dopamine hypothesis of
and Drug Interactions schizophrenia.
Generally, psychostimulants like amphet-
3.2.1 Methylphenidate. Methylphenidate
amine (7) and methylphenidate (8) can be
(Ritalin, 8) is widely prescribed for the treat-
used safely with most classes of medications
ment of ADHD. Approximately 90% of chil-
and with few contraindications (22). The
dren treated for ADHD are given methyl-
acute adverse reactions to stimulants can gen-
phenidate (30), representing about 2.8% of all
erally be understood from the perspective of
U.S. children aged 5-18 years (31). It is both
their pharmacology. Psychostimulants act as
well tolerated and efficacious in the treatment
indirect sympathomimetic agents; they either
of attention deficit hyperactivity disorder, and
directly release stored catecholamines, includ-
is associated with few serious adverse effects
ing those in peripheral adrenergic neurons re-
(32). Although there are rare reports of drug
sponsible for vascular tone, or else block their
interactions between methylphenidate and
reuptake. These actions affect the cardiovas-
certain other drugs, they are so infrequent
cular system in fairly predictable ways. In ad-
that there is no consistent pattern that can be
dition, cocaine produces a local anesthetic ef-
identified. Toxic concerns with methylpheni-
fect by the blockade of sodium channels (23).
date would principally revolve around the
Although this would normally be the pharma-
abuse of this drug to obtain a stimulant high,
cological basis for a class I antiarrhythmic
and the consequent possibility of developing
drug, it paradoxically induces proarrhythmia
dependency. A further concern with the long-
(24). term use of methylphenidate is the possibility
that patients may be at increased risk for psy-
chostimulant abuse. Although when taken
orally methylphenidate has a low euphori-
genic potential (33), when used intravenously
it has an abuse pattern and symptoms of tox-
icity similar to those of cocaine and amphet-
amine (34).
. . Recent studies in rats have also
In addition to acute effects, however, pro- shown that animals treated with methyl-
longed usage of amphetamines (and other psy- phenidate develop behavioral sensitization,
chostimulants) can produce an "amphetamine suggesting that human users may have in-
psychosis." This syndrome was first clearly creased susceptibility to psychostimulant
documented by Connell(25)and is regarded as abuse (35).
very similar to paranoid schizophrenia, char-
acterized by "paranoid psychosis with ideas of 3.2.2 Pemoline. Pemoline (91, an agent
reference, delusions of persecution, auditory used in treatment of ADHD, has been associ-
and visual hallucinations in a setting of clear ated with hepatotoxicity, with the majority of
consciousness" (25). The psychosis clears cases occurring in pediatric patients. From its
quickly after the drug is withdrawn. Psychosis marketing in 1975 up to 1989, 12 cases of
has been induced experimentally in normal acute hepatic failure and six deaths associated
subjects by continuous amphetamine admin- with pemoline hepatotoxicity had been re-
istration (26). Amphetamine psychosis has ported to the FDA (36). Death generally oc-
3 Clinical Use of Agents

(41, respectively, serve as the raw material for

the production of (-)-cocaine (3). The latter
was first isolated in 1860 and became medi-
cally important as an excellent local anes-
thetic agent, but one that is a potent and
highly addictive CNS stimulant. The acute
toxicity of cocaine derives primarily from its
intense sympathomimetic actions. In 1991 an
attempt was made to assess the intrinsic tox-
icity of cocaine by computing the incidence of
curred within 4 weeks of the onset of signs and adverse health outcomes per population of
symptoms of liver failure. In two recent cases, drug abusers. The rates of emergency depart-
pemoline-induced liver failure required liver ment visits and deaths were estimated at 15.1
transplantation (37). and 0.5, respectively, per 1000 persons using
drugs (40).
Cocaine can have marked effects on the
heart and cardiovascular system. Adverse ac-
tions may include myocardial ischemia, car-
diac arrhythmias, cardiotoxicity, hypertensive
effects, cerebrovascular events, and a hyperco-
agulable state (24,40). By 1997 more than 250
cases of mvocardial
" infarction related to the
recreational use of cocaine had been docu-
mented in the literature (41). Although less
common, aortic dissection related to use of co-
Although the absolute number of reported caine-free base ("crack cocaine") has also been
cases is not large, the rate of reporting is 4-17 documented (42). Seizures also can be associ-
times higher than that expected in the general ated with cocaine use (43).
population. This estimate may be conservative Acutely, cocaine can cause anxiety or panic
because of underreporting and because the reactions. Used chronically, cocaine can in:
long latency between initiation of pemoline duce a psychosis that closely resembles that
treatment and the occurrence of hepatic fail- produced by amphetamine. It is generally con-
ure may limit recognition of the association. If sidered that amphetamine psychosis predom-
only a portion of actual cases was recognized inantly mimics the positive symptoms of
and reported, the risk could be substantially schizophrenia, but in fact stimulant-induced
higher. By contrast, a meta-analysis of the lit- psychosis can mimic a broad range of symp-
erature by Shevell and Schreiber (38)suggests toms, including negative and bizarre symp-
that the risk of acute hepatic failure may be an toms (44). Paranoid behavior has been pro-
overestimate. Nevertheless, because of its as- duced in experienced cocaine users by
sociation with life-threatening hepatic failure, continuous (4 h) cocaine infusion (45).
pemoline should not ordinarily be considered In addition to these physiological toxicities,
as a first-line therapy for ADHD. In fact, cocaine addicts suffer from a variety of social
pemoline has been withdrawn from the Cana- and economic problems that result in tremen-
dian market as a result of this toxicity (39). dous costs to society. Many of the estimated
1.5 million cocaine addicts in the United
3.2.3 Cocaine. The coca plant is a small States (see, are un-
shrub or tree that is indigenous to South deremployed, and if they are employed at all,
America, where for centuries the leaves have they are likely to be involved in drug distribu-
been chewed by the local native populations. tion activities, and typically perform marginal
The dried leaves of Eythroxylum coca roles in the legal economic system (46, 47).
Lamarck, or E. truxillense Rusby, commer- Adults in such drug-using households rarely
cially known as Huanuco coca, or Truxillo coca engage in conventional behaviors, and often
CNS Stimulants

parent children by using conduct norms that correspond to functional antagonism of this
are structured to produce individuals who receptor, similar to the effects of caffeine (57).
have reduced chances to become conventional 3.3 Absorption, Distribution, Metabolism,
adults (48). and Elimination
3.2.4 Caffeine. The psychostimulant ac- All substituted amphetamines are strong or-
tion of caffeine generally is accepted as well ganic bases, with pKa values ranging from 9.5
established. Caffeine quickens reaction time to 10 (58). The pKa of both cocaine and phen-
and enhances vigilance, increases self-rated metrazine is somewhat lower, at 8.5, and
alertness, and improves mood. There is, how- methylphenidate has a pK, of 8.8 (58). Thus,
ever, little unequivocal evidence to show that these bases are all significantly protonated at
physiological pH. Binding to their biological
regular caffeine use is likely to benefit sub-
targets also probably occurs with the proton-
stantially either mood or performance. In-
ated species [e.g., (5911. These drugs are all
deed, one of the significant factors motivating
administered as their water-soluble salts, usu-
caffeine consumption appears to be "with- ally as hydrochlorides or sulfates. At physio-
drawal relief" (49). logical pH, of course, these bases exist in an
Caffeine can produce adverse and unpleas- equilibrium between the protonated ionized
ant effects if doses are increased. Caffeine has form and the unprotonated un-ionized spe-
weak reinforcing properties, but with little or cies. The latter free bases are relatively lipid
no evidence for upward dose adjustment, pos- soluble and readily penetrate the brain, where
sibly because of the adverse effects of higher they exert their CNS stimulant effects. Many
doses. Withdrawal symptoms, although rela- of these drugs are eliminated in the urine un-
tively limited with respect to severity, do oc- changed because acidic urine leads to a higher
cur, and may contribute to continued caffeine fraction of protonated species, thus decreasing
consumption (50). Health hazards are small if reabsorption of the unchanged drug in the re-
any, and caffeine use is not associated with nal tubules. Decreasing urinary pH by, for ex-
incapacitation (51). Acute intake of caffeine ample, administering ammonium chloride
increases blood pressure, with the strongest leads to the anticipated increased urinary ex-
pressor response in hypertensive subjects. cretion and reduced duration of action (60). A.
Some studies with repeated administration of comparison has been reported of the urinary
caffeine have shown a persistent pressor ef- excretion pattern of methamphetamine in hu-
fect, whereas in others chronic caffeine inges- mans, guinea pig, and rat (61). In humans,
tion did not increase blood pressure (52). 23% of the dose was excreted unchanged.
Epidemiologic studies have produced contra- Ring-hydroxylated and N-demethylated me-
dictory findings regarding the association be- tabolites were excreted as 18 and 14%of the
tween blood pressure and coffee consumption. dose, respectively.
Duringregular use, tolerance to the cardiovas-
cular responses develops in some people, and 3.3.1 Amphetamine Metabolism. The me-
therefore no systematic elevation of blood tabolism of (+)-amphetamine (10)is variable,
pressure can be shown either in long-term or depending on the species studied. Possible
in population studies. Thus, regular caffeine metabolic transformations involve hydroxyl-
consumption may be harmful to some hyper- ation at the a or p side-chain carbon atoms,
tension-prone subjects (52). The hemody- the nitrogen atom, and thepara position ofthe
namic effects of chronic coffee and caffeine aromatic ring. These metabolites would then
consumption have not been sufficiently be further oxidized, or conjugated and ex-
studied. creted. One or more of these pathways pre-
Finally, caffeine may provoke a panic at- dominates, depending on which animal spe-
tack in individuals who suffer from panic or cies is being studied. In humans, the half-life
anxiety disorders (5356). Recently, an aden- of (+)-amphetamine has been reported as 7 h
osine &, receptor knockout mouse has been (62). About 30% of the dose of racemic am-
developed that has behavioral symptoms that phetamine is excreted unchanged, and acidifi-
3 Clinical Use of Agents

cation of the urine can decrease the half-life methylphenidate to between 10% and 50%
significantly (63,641.In humans, the principal (68). Ritalinic acid is not pharmacologically ac-
metabolite is benzoic acid (65). The details of tive. A ring-hydroxylated ritalinic acid metab-
the sequences of metabolic reactions of am- olite (2%) has also been identified. Other mi-
phetamine that lead to benzoic acid have not nor pathways involving oxidation of the
been elucidated (62), but the P-hydroxylated piperidine ring (0x0-ritalin) and conjugation
metabolite, norephedrine, has also been iden- reactions represent less than about 1%of the
tified as a metabolite in humans (66). administered dose (30).
The metabolism of methamphetamine (11)
involves both N-demethylation and ring hy- 3.3.3 Cocaine Metabolism. Because co-
droxylation. Caldwell et al. (61) reported that caine (3)has two ester functions, both can be
23% of the administered dose was excreted as hydrolyzed in vivo to generate metabolites.
unchanged drug, 18% as the 4-hydroxylated Hydrolysis of the methyl ester leads to benzo-
compound, and 14% as the N-demethylated ylecgonine (12), and hydrolysis of the benzoyl
amphetamine. ester leads to ecgonine methyl ester (13). Tro-
pan-3P-01-2P-carboxylicacid is known as ecgo-
3.3.2 Methylphenidate Metabolism. The me- nine (14). In cocaine users who also consume
tabolism and pharmacokinetics of methyl- significant amounts of ethanol, a transesteri-
phenidate have been studied extensively. fication product (cocaethylene, 15) is also de-
Methylphenidate (8)is administered as the ra- tected. Cocaethylene is also a potent psycho-
cemic threo isomer, but the (-)-threo enantio- stimulant, with about four times higher
mer is more rapidly metabolized. potency as a local anesthetic than that of co-
Methylphenidate is an ester, and the caine itself (69),and can enhance the cardio-
methyl ester is rapidly cleaved. The ester hy- toxicity associated with cocaine use.
drolysis product, called ritalinic acid, com-
prises about 80% of the urinary metabolites 3.3.4 Diethylpropion Metabolism. Diethyl-
after an orally administered dose (67). The la- propion (16) is used most extensively as an
bility of the ester function is probably the ma- appetite suppressant. It possesses the core
jor factor limiting the oral bioavailability of phenethylamine structure characteristic of
CNS Stimulants

many psychostimulants, but is a tertiary arni- apparently N-dealkylated readily and, thus,
noketone. It is extensively metabolized in hu- the principal metabolite is the N-deethylated
mans, with only about 3-4% of the drug ex- compound (17),constituting about 35%of the
creted unchanged. a-Alkylaminoketones are administered dose. Reduction of the carbonyl
4 Physiology and Pharmacology

is less important, with about 20% of the dose begun to focus attention on glutamate sys-
going that route, to afford N,N-diethyl- tems as potential key components of the ac-
norephedrine. About 30% of the dose cannot tions of psychostimulants. For example,
be accounted for as an amine product in the Swanson et al. (79) have shown that re-
urine and is probably a deaminated metabolite peated cocaine administration leads to long-
(70).Studies by Yu et al. (71) found that the term attenuation of group I metabotropic
N-deethylated metabolite (17) was probably glutamate receptor function in the nucleus
responsible for the pharmacological effects of accumbens. In particular, this functional re-
diethylpropion (16). These workers reported duction was related to significantly reduced
that the N-monoethyl metabolite (17) was a mGluR5 immunoreactivity in the medial nu-
substrate at the norepinephrine and serotonin
cleus accumbens. Even more exciting is the
transporters and an inhibitor at the dopamine
recent report that mGluR5 knockout mice
uptake transporter, whereas (1R,2S) and
(1S,2R)-N,N-diethylnorephedrine as well as do not display the reinforcing and locomotor
diethylpropion itself were inactive in those as- effects of cocaine, in spite of the fact that
says. cocaine administration increases extracellu-
lar dopamine in the nucleus accumbens of
these mice to levels that do not differ from
4 PHYSIOLOGY A N D PHARMACOLOGY those of wild-type animals (80).In the near
future, the role of glutamate systems in the
4.1 Where and How These Drugs Work
actions of psychostimulants will no doubt be
Neurons in the central nervous system com- more fully elucidated, resulting in new ap-
municate by chemical transmission. Of rele- proaches to the treatment of conditions that
vance to the present discussion are mono- now respond to classical stimulants.
amine neurons that release dopamine, There are two principal mechanisms for in-
norepinephrine, or serotonin as one of their creasing synaptic monoamine levels. One is to
transmitters in response to an action poten- block the reuptake of neurotransmitter after
tial. Reuptake transporter proteins embedded its excitation-coupled release from the neuro-
in the neuronal plasma membrane then clear nal terminal. Thus, blocking the action of the
the synapse of monoarnines, typically taking uptake carrier protein prevents clearance of
up 70-80% of the released transmitter. This the neurotransmitter from the synapse, leav-
reuptake is thought to be the major termina- ing high concentrations in the synaptic cleft
tion mechanism for the monoamine chemical that can continue to exert a signaling effect.
signaling process. This mechanism is the one invoked to explain
All psychostimulants appear to elevate the action of cocaine, a potent inhibitor of
synaptic levels of dopamine and norepineph- monoamine reuptake at the dopamine, seroto-
rine. In addition, cocaine and, to a lesser ex- nin, and norepinephrine transporters, and of
tent, some of the other agents also raise syn- methylphenidate, which is a reuptake inhibi-
aptic levels of serotonin. It is the current tor at the dopamine and norepinephrine
consensus that elevated dopamine levels transporters (81).It should be noted, however,
lead to CNS stimulation and are responsible that methylphenidate also has the ability to
for the reinforcing properties of stimulants induce the release of catecholamines stored in
(72-78). Nevertheless, recent studies have neuronal vesicles (82,83).
180 CNS Stimulants

Figure 4.1. Amphetamine interacts with the dopamine transporter protein (1)and is transported
inside. Na+ and C1- are cotransported, and Kf is countertransported in the process. After being
transported inside the terminal, high concentrations of amphetamine can displace dopamine from
vesicular storage sites (2),leading to elevated cytoplasmic levels of dopamine (3).After amphetamine
dissociates on the intraneuronal surface, dopamine binds to the carrier (4). The carrier then trans-
ports dopamine to the extracellular face (5), driven by the favorable concentration gradient, where
the dopamine dissociates and leaves the carrier available for another cycle.

The second mechanism is the one more rel- uptake. Not surprisingly, cocaine and amphet-
evant to the action of amphetamine and re- amines have effects on the cardiovascular
lated agents. This mechanism is illustrated in system, by virtue of their ability to enhance
Fig. 4.1. Amphetamine, and other small mo- indirect adrenergic transmission at peripheral
lecular weight compounds with similar struc- sites. Knowledge of the physiology of the sym-
tures, are substrates at the monoamine up- pathetic nervous system and the functions of
take carriers and are transported into the peripheral adrenergic nerve terminals allows
neuron. The uptake carrier has an extracellu- a relatively straightforward prediction of the
lar and intracellular face, and after transport- types of drug effects possessed by monoamine
ing a substrate (amphetamine, etc.) into the uptake inhibitors or releasing agents.
neuron, the intracellular carrier face can bind
to dopamine and transport it back to the ex- 4.2 Biochemical Pharmacology: Receptor
tracellular face. This exchange diffusion Types and Actions
mechanism is calcium independent, and is ca-
pable of robustly increasing synaptic trans- The monoamine reuptake carrier proteins
mitter levels. This process is often described (targets of the psychostimulants) are mem-
as a "reversal" of the normal uptake carrier bers of a larger Nat/C1- transporter family
process. that includes a number of other proteins, in-
Whereas the CNS stimulant effects of these cluding the GABA transporters, amino acid
molecules depend on an action in the brain, transporters, and orphan transporters (84).
uptake inhibitors and substrates at peripheral The primary amino acid sequence of the
monoamine carrier sites can obviously exert monoamine transporters is highly conserved,
other physiological effects. Cocaine is an excel- with several regions of these proteins having
lent local anesthetic agent. Furthermore, its high homology. It is presently believed that all
potent inhibition of norepinephrine reuptake of the members of this family possess a mem-
leads to stimulation of a-adrenergic receptors, brane-spanning 12 a-helix motif, with a single
causing local vasoconstriction that delays the large loop containing glycosylation sites on the
diffusion of the anesthetic agent out of the tis- external face of the membrane (Fig. 4.2).
sue. Similarly, users who chronically insuf- Members of this family of proteins have been
flate cocaine into their nasal passages often identified not only in mammalian species, but
develop necrotic lesions as a result of the local also in eubacteria and archaebacteria, indicat-
vasoconstricting effect of cocaine, again aris- ing their very early emergence in the evolution
ing from the blockade of norepinephrine re- of life.
gy and Pharmacology 181

-e 4.2. Representation of the 12-helix transmembrane transporter protein family. Both the
I- and the carboxyl-terminus are intracellular, with the second extracellular loop being larger,

messing glycosylation sites. [Adapted from Nelson (84).1

uman norepinephrine uptake trans- stimulant drug of interest. The imaging tech-
1s first sequenced and then expressed nique then is used to determine how much of
cells in 1991 (85) and found to have the labeled ligand has been displaced from its
IS identical to those of the native receptors by competition from increased ex-
ber. The cloning and sequencing of tracellular endogenous dopamine. Based on
nine transporter (86-88) and the se- the known affinity of the labeled ligand for its
ransporter (89, 90) were reported in dopamine receptor, calculations can be used to
year. There are a number of excel- determine the increased concentration of do-
!w articles written about monoamine pamine that must have been available at the
;ers (84, 91-93). receptors. These definitive studies have
lacological studies of the mechanism clearly established a role for dopamine in the
For psychostimulants in animals have effects of stimulants in humans (72, 74).
liformly pointed to the importance of This type of approach has recently been ap-
pathways for the increases of loco- plied to the study of methylphenidate. For ex-
tivity and reinforcing properties (94, ample, Booij et al. (96) used SPECT imaging
:onclusions of those studies have gen- and an [1231]benzamidedopamine D, receptor
!n extrapolated to humans, with little ligand antagonist ([123111BZM)to measure sig-
vidence until recently to clearly sup- nificant displacement of the ligand by endoge-
e ideas. In the past several years how- nous dopamine that had been released in re-
ical studies of several stimulants, us- sponse to administration of methylphenidate.
yo brain imaging either with single In related work, Volkow et al. (74) used [llC]-
lission computed tomography (SPECT), (+I-threo-methylphenidateto show that greater
)n emission tomography (PET) tech- than 80% occupancy of the dopamine trans-
lave provided evidence for elevated porter was required to produce the stimulant
~ l adopamine
r in response to psycho- "high." With the dopamine D, receptor antag-
t administration. In essence, these onist [llClraclopride, Volkow et al. (97, 98)
!mploy either a single photon- or showed that the intensity of the methylpheni-
emitting dopamine receptor antago- date "high" was quantitatively correlated
labeled antagonist is administered with the levels of released dopamine and dopa-
ie absence and in the presence of the mine D, receptor occupancy. Subjects who
CNS Stimulants

perceived the most intense high had the high- postsynaptic receptor isoforms that are impor-
est increases in extracellular dopamine. Con- tant in the various actions of psychostimu-
versely, no high was experienced by subjects lants.
when methylphenidate did not increase dopa-
mine levels. In a second study, using the same 4.2.1 A Role for Serotonin. Although the
methodology, this same group (99) found that conventional wisdom is that stimulants ele-
subjects who "liked" the effects of methyl- vate synaptic dopamine, it is not at all clear
phenidate had significantly lower dopamine that this sole mechanism is responsible for the
D, receptor levels than those of subjects who spectrum of effects seen with the psycho-
disliked its effects. The authors speculated stimulants. In addition, it is becoming evident
that lower D, receptor density might be a fac- that animal models used to understand the
stimulants must consider mechanisms under-
tor contributing to psychostimulant abuse, by
lying effects on locomotor activity somewhat
providing a more pleasurable response. These
differently from those that govern either re-
imaging studies illustrate how data from ani-
ward or drug discrimination phenomena (101,
mal research can now be validated in humans. 102). The use of mice genetically deficient for
Because the stimulants cause increased the serotonin or dopamine transporter
synaptic levels of dopamine, and other mono- ("knockout mice") has produced some partic-
amine neurotransmitters, they indirectly lead ularly interesting findings. For example,
to stimulation of various postsynaptic recep- knockout mice lacking the DA transporter
tors, through the increased concentrations of have high levels of extracellular dopamine, a
neurotransmitter. A large number of animal condition that would presumably mimic the
studies have been reported that used various pharmacological action of cocaine and display
agonists and antagonists to elucidate the role spontaneous hyperlocomotion (103). Surpris-
of different dopamine receptor isoforms. Until ingly, these mice still self-administered co-
recently, however, only nonspecific ligands caine (104). Further experiments in these
(i.e., with effects on both the Dl-like and D,- mice indicated the probable involvement of
like families) were available. In drug discrim- the serotonin transporter. In addition, condi-
ination studies, rats have been trained to rec- tioned place preference, another animal model
ognize and discriminate the interoceptive cue of the reinforcing quality of a drug, could be
produced by injection of amphetamine or co- established for cocaine in mice lacking either
caine (100). Administration of a partial but the dopamine transporter or the serotonin
selective Dl-receptor agonist SKF 38393 was transporter (105). Place preference could also
partially recognized by these cocaine-trained be established for methylphenidate, another
stimulant that is thought to work through do-
rats, but not by amphetamine-trained ani-
pamine mechanisms, in mice lacking the dopa-
mals. Yet, both amphetamine- and cocaine-
mine transporter.
trained rats discriminated the cue produced
Experiments with knockout mice often
by a dopamine D, agonist bromocriptine as produce unexpected results. It must be kept in
being similar to their training drugs. A dopa- mind, however, that when a key protein is
mine D,-selective agonist produced cocaine re- missing during neural development, the off-
sponses, but was only partially recognized by spring often have some type of adaptation that
amphetamine-trained rats. Following addi- is not seen in the wild-type organism. Some
tional experiments with dopamine receptor caution, therefore, must be exercised in inter-
subtype selective antagonists, the authors preting the results. For example, Belzung et
concluded that the dopamine D, receptor al. (106) found that mice lacking the serotonin
played an essential role, but that both the Dl 5-HT,, receptor failed to display conditioned
and D, receptors might have some less impor- place preference. However, when these knock-
tant function. There is an extensive present out mice were compared in studies using clas-
research effort under way in many labora- sical pharmacological antagonists of the
tories that is attempting to elucidate both 5-HT,, receptor, divergent results were ob-
the anatomical substrates and the specific tained. The 5-HT,, receptor knockout mice
4 Physiology and Pharmacology

had an increased locomotor response and in- their ability to release NE, and not DA. Fur-
creased propensity to self-administer cocaine ther, their ranking in subjective effects did not
(107). By contrast, a 5-HT,, receptor antago- correlate with decreased plasma prolactin, a
nist attenuated cocaine-induced locomotor ef- response that is mediated by dopamine recep-
fects but had no effect on cocaine self-admin- tor stimulation. These authors suggested that
istration (108). The authors point out that NE might contribute to the amphetamine-like
compensatory changes during development of psychopharmacology of stimulants, at least in
the knockout mice may have rendered them humans.
more vulnerable to the effects of cocaine. In a related vein, the subjective psycho-
Nonetheless, there is a vast body of litera- stimulant effects of amphetamine were atten-
ture documenting interactions between dopa- uated following a 2-h pretreatment with a ty-
mine and serotonin pathways in the brain rosine- and phenylalanine-free amino acid
(109-111). Clearly, however, if a drug (e.g., mixture (118).These amino acids are biosyn-
cocaine) releases multiple transmitters, then a thetic precursors of the catecholamines, and
behavioral interaction is not surprising. Inhi- deprivation would be expected to produce
bition of presynaptic reuptake of serotonin, transient reductions in endogenous dopamine
for example, could lead to postsynaptic activa- and norepinephrine. The authors concluded
tion of a variety of other receptors, some of that tyrosine depletion attenuates the release
which could modulate dopamine function. In of dopamine required for the psychostimulant
addition to potential effects on 5-HT,, recep- effect. Interestingly, the pretreatment did not
tors, other studies have implicated serotonin reduce the subjective appetite-suppressant
5-HT, receptors (112), 5-HT,, receptors (anorectic) effect of amphetamine. The study
(113),and 5-HT,, receptors (114). 5-HT,, re- authors attributed this latter finding to a con-
ceptors can also modulate the locomotor ef- tinued release of norepinephrine by amphet-
fects of cocaine (115). amine. Tyrosine depletion, however, would
also attenuate norepinephrine biosynthesis
4.2.2 A Role for Norepinephrine. Although and it may be more reasonable to conclude
the vast majority of studies of psychostimu- that the anorectic effect might be related to
lants have focused on the role of dopamine the often-overlooked ability of amphetamine
andlor serotonin, the importance of norepi- to release neuronal serotonin.
nephrine (thought to be paramount 30 years This chapter makes no attempt to review
ago) is generally now overlooked. Details of all the literature that focuses on the role of
the mechanism of action of psychostimulants norepinephrine and serotonin in the actions of
have been developed primarily through the psychostimulants. At the time of this writing,
use of animal models, in which dopamine the general consensus seems to be that effects
seems to be the key player, and these results on dopamine systems are necessary, but per-
then have been extrapolated to humans. Yet, haps not sufficient, conditions to explain all
cocaine also is a potent NE uptake inhibitor, the different actions of stimulants. There ap-
and the potency of amphetamine for norepi- pears to be increasing awareness, spurred ini-
nephrine release is similar to that for dopa- tially by studies of cocaine, that serotonin may
mine release. Indeed, in the rat prefrontal cor- be a much more important player than was
tex, amphetamine and cocaine increased heretofore recognized. In the next few years
extracellular norepinephrine to an extent that this role likely will be studied and elucidated
was quantitatively similar to that of dopamine in much greater detail.
(116).Further, it appeared that the increase in The role of norepinephrine in the actions of
prefrontal cortical norepinephrine was actu- stimulants has largely been overlooked, al-
ally attributable to the blockade of the norepi- though a few studies suggest that this trans-
nephrine transporter by both drugs. Recently, mitter may be of major significance. On the
Rothman et al. (117) reported that the oral other hand, until clinical studies are carried
doses of several stimulants required to pro- out using receptor blockers and specific nor-
duce amphetamine-like subjective effects in epinephrine transporter inhibitors, this area
humans were most closely correlated with will remain muddy, at best. In virtually every
CNS Stimulants

example, from amphetamine to cocaine, the of locomotor activity in animal models, studies
compounds have significant effects at the nor- have implicated the dopamine D, receptor
epinephrine transporter, in some cases equal (129, 130). It has not been clear, however,
to, or even greater than, those at the dopamine whether effects mediated by striatal adeno-
transporter. When behavioral or mood changes sine &, receptors absolutely depend on the
are correlated with levels of extracellular do- presence of dopamine D, receptors. To study
pamine, and dopamine is highly correlated this problem, Chen et al. (131) employed ge-
with changes in extracellular norepinephrine, netic knockout mice deficient either in dopa-
one cannot be certain which underlying phar- mine D, receptors or adenosine &, receptors,
macology is ultimately more important with- or a double knockout mouse deficient in both
out experiments using specific blockers of both types of receptors. These studies found that
dopamine and norepinephrine transporters A, receptors may affect neuronal activity in a
and receptors. It may be that effects on dopa- manner that is partially independent of the
mine are necessary, but not sufficient, and presence of dopamine D, receptors, such that
that both norepinephrine and serotonin play endogenous adenosine may be most accu-
modulatory roles. Because the stimulants rately viewed as a facilitative modulator of
have such diverse effects, including increasing striatal neuronal activity rather than simply
activity, mood, appetite suppression, and so as an inhibitory modulator of D, receptor
forth, it seems likely that serotonin and nor- neurotransmission.
epinephrine play more or less important mod- These studies, and many others, conclude
ulatory roles, depending on which aspects of that the acute locomotor stimulant effects of
the specific drug's effects are being studied. caffeine in animal models are mediated in part
Caffeine and the other methylxanthines in- by dopaminergic systems and dopamine recep-
hibit phosphodiesterases, the enzymes that tors. Recent studies suggest that tolerance to
degrade CAMP.For many years it was believed the locomotor stimulant effects of chronic caf-
that the stimulant effect of caffeine was attrib- feine may also be related to specific changes in
uted to this enzyme inhibition. At the plasma dopaminergic function (128). Thus, in spite of
concentrations obtained after two to three the fact that methylxanthines are structurally
cups of coffee ( ~ 1 @),
0 however, antagonism different from other psychostimulants, and do
of adenosine A, (and A,) receptors in brain is not directly affect dopamine transporters or
believed to be the most relevant action to ex- receptors, in fact their stimulant action is de-
plain the stimulant effects of caffeine (119, rived from effects on central dopamine path-
120). Perhaps not surprisingly, in view of ear- ways.
lier discussion in this chapter, caffeine admin-
istration has been shown to lead to elevated
levels of brain dopamine (121, 122). It is
thought that adenosine receptor stimulation
Examination of the structure-activity rela-
facilitates GABA- or acetylcholine-mediated
tionships (SARs)of several of the classic stim-
inhibition of dopamine receptors in striatopal-
ulants provides not only an understanding of
lidal and striatonigral neurons (123), with the
the development of other drugs, but provides
end result of decreased dopaminergic func-
important clues as to the underlying mecha-
tion; adenosine antagonists would thus have a
nisms involved in interaction with the target
reverse action. Many studies have examined
protein(s). The following sections will hope-
the interaction between adenosine A,, recep-
fully illustrate both of these points.
tors and dopamine receptors, both of which
are highly concentrated and colocalized in the
5.1 Amphetamine
striatum and have reciprocal antagonistic in-
teractions (124-127). There is abundant evi- There are a number of related structures that
dence for pre- and postsynaptic interactions are often referred to as "amphetamines," al-
between adenosine and dopamine receptors, though the name amphetamine refers to one
by which adenosine inhibits doparninergic ac- specific molecular entity. Grouped in this class
tivity [e.g., (128)l. With respect to stimulation would be (+)-amphetamine (101,N-methyl-
5 Structure-Activity Relationships

: amphetamine [S-(+)-methamphetamine, 181,

phentermine (19), phenmetrazine (Preludin,
20), and phendimetrazine (21). Diethylpro-
pion (Tenuate; 16) is used as an appetite sup-
pressant and, although it has the amphet-
amine skeleton, its effects are much weaker as
a stimulant than those of the other structures
listed here. The stereochemistry at the a side-
chain methyl group is the same for the most
potent enantiomer of each structure, although
the pure enantiomer has not generally been
marketed except for the cases of (+)-amphet-
amine (10)and (+)-methamphetamine (18).

5.1.1 Length of the Side-Chain. The length

of the side-chain is limited to two carbon at-
oms (134, 135). That is, for transporter sub-
strates, the optimum pharmacophoric tem-
plate appears to be a basic nitrogen two carbon
atoms removed from an aromatic ring system.
This observation of course is not too surpris-
ing, given that the transporter substrates do-
pamine, norepinephrine, and serotonin all
bear this essential core.

5.1.2 Nitrogen Substituents. Nitrogen sub-

stituents are very limited. The primary amine
(amphetamine)and the N-methylamine (meth-
amphetamine) are the most potent com-
pounds (135). An N-methyl increases the po-
tency of both amphetamine and cathinone (2)
(136). Larger alkyl groups (135, 137) or N,N-
dialkylation, either dramatically attenuate or
completely abolish stimulant activity (138).
Nevertheless, N,N-dimethylamphetamine has
appeared on the illicit market (139) and does
appear to have behavioral effects in rats and
The structural requirements of the dopa- monkeys similar to amphetamine (138, 140).
mine (and norepinephrine) transporter ap- The rapid onset of action suggested that the
pear to be fairly rigid. There is very little mo- N,N-dimethyl compound itself had pharmaco-
lecular variation that is tolerated without logical effects, rather than the N-demethyl-
significant loss of activity. The relatively lim- ated metabolite, methamphetamine, although
ited information that is available, mostly from the latter is one of the known metabolites of
animal studies, can be summarized by consid- N,N-dimethylamphetamine (141).
ering the various areas of substitution for a Active metabolites may be much more im-
general phenethylamine structure. These portant in N,N-dialkylated compounds that
structure-activity relationships have been re- possess a p-keto function, as in cathinone (2).
cently surveyed (132), and an extensive and In that case, the N,N-dimethyl compound is
comprehensive review by Biel and Bopp (133) nearly as active as the N-monomethyl com-
covered the older literature. pound (142). It is known, however, that the
CNS Stimulants

alkyl groups of p-aminoketones are readily leling the potency difference found with the
cleaved metabolically. Thus, the N,N-di- enantiomers in vitro, using rat brain striatal
methyl cathinone analog is likely converted in synaptosomes (149). The two isomers were of
vivo to the N-monomethyl compound meth- nearly equal potency in their effects on norepi-
cathinone. This argument is based on evi- nephrine accumulation by rat hippocampal
dence that for diethylpropion, the N,N-diethyl synaptosomes (149). This stereochemical re-
congener of cathinone, it is the N-monoethyl quirement applies to p-keto derivatives as
metabolite that is the active species (70, 71). well; the corresponding active isomer has the
Although longer N-alkyl groups lead to less S-(-) configuration (136).
active compounds, one exception to this gen-
eralization is benzphetamine (Didrex),N-ben- 5.1.4 The a-alkyl Substituent. The a-alkyl
zyl-N-methylamphetamine (22). Despite the group cannot be much larger than a methyl.
N,N-dialkyl groups in benzphetamine, in hu- Phenethylamine itself, lacking the side chain
mans it produces subjective effects character- a-methyl group, is inactive in vivo because of
istic of amphetamine-like drugs such as phen- its rapid inactivation by monoamine oxidase.
metrazine (20) (143). Althoughpara-hydroxy- Addition of the a-methyl group retards metab-
N-benzylamphetamine is a major metabolite olism by this route, leading to the orally bio-
of benzphetamine, methamphetamine and available drug amphetamine. The uptake
amphetamine are also detectable in urine and transporter, however, cannot tolerate large
hair following administration of benzphet- groups in this region and the a-ethyl analogs
m i n e (144-146). It is not clear from the liter- of both amphetamine and methamphetamine
ature whether the reinforcing effects of benz- had markedly attenuated activity in a drug
phetamine are attributable to metabolic discrimination assay with rats trained to dis-
formation of amphetamine or methamphet- criminate (+)-amphetamine (150). a,a-Di-
amine. Based on the studies with N,N-dimeth- methyl groups, as in phentermine (19),
ylamphetamine by Witkin (138),however, one though giving an active compound, still reduce
would predict that the parent molecule has activity.
some pharmacological activity. Attempts to incorporate the side chain into
ring structures also led to compounds with at-
5.1.3 Stereochemistrv at the a Carbon. tenuated activity. For example, in drug dis-
The stereochemistry at the a carbon atom, crimination assays using rats trained to recog-
when enantiomers exist, is homochiral to that nize the effect of (+)-amphetamine (lo),
of S-(+)-amphetamine (lo), shown earlier. compounds (23) and (24) either failed to pro-
Both the releasing actions at dopamine and duce amphetamine like effects, or had much
norepinephrine transporters in isolated rat lower potency (150, 151). When n = 3, the
brain slices (147) and the locomotor and ste- compound lacked any amphetamine-like ac-
reotypic effects in rodents (148) are more po- tion.
tently affected by the S-(+) isomer of amphet-
amine than by the R-(-1 isomer. In this latter 5.1.5 Other Side-Chain Substitutions. Lim-
study, the (+) enantiomer was about five ited substitution of the side chain is tolerated.
times more potent than the (-1 isomer, paral- A p-hydroxy group on methamphetamine
5 Structure-Activity Relationships

substitution decreases their potency at these

sites. The serotonin carrier is relatively pro-
miscuous and tolerates a variety of ring sub-
stituents, many of which dramatically in-
crease the potency at the serotonin carrier
from that of amphetamine itself. No ring mod-
ifications are known that give rise to a substi-
tuted amphetamine that completely retains
gives ephedrine (I), shown earlier. Although amphetamine-like psychostimulant activity.
ephedrine is a CNS stimulant, its effects are para- Fluoroamphetamine (26; X=F) has
much weaker than those of methamphet- been reported to have effects in rats resem-
amine. Similarly, addition of a P-hydroxy to bling those of amphetamine, but substitution
amphetamine gives phenylpropanolamine, a with larger halogens (e.g., chloro or iodo) leads
compound that is nearly devoid of CNS stim- to compounds that have significant serotonin
ulant effects. One may speculate that the polar releasing potency, and that produce behav-
hydroxy group reduces the hydrophobicity of ioral effects that are different from those of
these compounds such that CNS penetration amphetamine itself (154).
is much reduced. The N-methyl of ephedrine
increases lipid solubility, so ephedrine has a
greater CNS action than that of phenylpropa-
nolamine. Addition of a keto function to the
structure of amphetamine or methamphet-
amine gives cathinone (2) or its corresponding
N-methyl derivative, methcathinone, the lat-
ter of which also has greater potency than that
of the primary m i n e (142). It should be noted 5.2 Methylphenidate
that an oxygen at the P position can be incor- The R,R-(+)-stereoisomer of methylpheni-
porated into a heterocyclic ring as in phen- date (8)is known to be the more active (155)
metrazine (20) and phendimetrazine (21). and is often referred to as the active "threo"
Methyl aminorex (25) is also a potent stimu- isomer. The (-)-enantiomer and the erythro
lant that incorporates the essential features of stereoisomers are much less potent. One study
the amphetamine template into an oxazoline has reported a series of aromatic ring-substi-
ring. The 4S,5S-trans isomer shown (25) is tuted analogs. The most potent compounds in
the most potent of the four possible stereoiso- that report were halogen substituted in the 3-
mers (152, 153). or 3,4- positions of the ring. For example, the
dichloro compound (27) was 32-fold more po-
tent than methylphenidate itself in inhibiting
dopamine reuptake (156). That finding paral-
lels a recent report by Deutsch et al. (1571,
that replacing the phenyl ring with a P-naph-
thy1 moiety (158) gave a compound with about
eightfold higher affinity for the dopamine
transporter. Those workers also reported that
the corresponding a-naphthyl analog had only
about one-tenth the potency of methylpheni-
date at the DAT. Taken together, these latter
5.1.6 Aromatic Ring Substitution. Simple observations indicate that the DAT must have
ring substituents can change the targets of the a hydrophobic region that generally extends
amphetamines from one monoamine uptake from the 3,4- positions of the aromatic phenyl
carrier to another. The dopamine and norepi- ring of methylphenidate.
nephrine uptake carrier proteins have the Deutsch et al. (157) also examined the ef-
most stringent structural demands, and any fect of heterocyclic ring size. The pyrrolidyl
CNS Stimulants

will not be presented. A useful perspective on

the SAR of cocaine analogs as it was under-
stood in 1992 has been presented by Carroll et
al. (159), with more a recent update in 1997
An attempt will be made here to distill down
the essence of the SAR of cocaine as it relates to
its stimulant properties. In many cases, com-
pounds have been reported that have not been
tested in vivo, but have only been compared for
affinity at the monoarnine transporters or in an
in vivo assay. Some of these data will be summa-
rized if they are reported in the context of the
stimulant effects of cocaine. Similarly, there
have been numerous attempts to develop co-
caine analogs that may bind to the dopamine
transporter and actually block the stimulant or
reinforcing effects of cocaine itself, in efforts to
develop treatments for cocaine addiction. This
chapter largely ignores many of those studies
and azepino, as well as the azacyclooctane con-
unless they contain in vivo data suggesting they
geners, were significantly less potent than
are relevant to a discussion of stimulant effects.
methylphenidate itself. That report also con-
Nevertheless, because stimulant properties
tained data for the morpholine analog of
have been associated with binding to the DAT, a
methylphenidate (158),which had an approx-
good deal of the SAR discussion here must be
imately 15 times lower affinity at the DAT.
discussed in the context of in vitro DAT affinity.
Beyond the studies cited here, very little addi-
A consideration of the structure-activity re-
tional SAR work has been done with methyl-
lationships of cocaine can focus on a number of
phenidate. key elements in the structure, as indicated be-
low. Each of the following sections includes a
5.3 Cocaine
discussion of the particular numbered struc-
Of all the psychostimulants, cocaine has prob- tural element.
ably been most studied, particularly within
the last decade, as a result of its widespread
abuse. Structure-activity studies have been
carried out with numerous analogs, not only
to elucidate the molecular requirements for
interaction with the various monoamine
transporters, but also in attempts to develop
treatments that might be useful for cocaine
addiction. Ideally, understanding the struc-
ture-activity relationships will be useful to un-
derstanding the functional topography of the
binding site of the transporters, and, if a
three-dimensional structure of the transport-
ers can be developed, these features would
map onto the binding site. Nevertheless, be-
cause the topic of this chapter is stimulants,
and not the structure-activity relationships of
monoamine transporters, an exhaustive sum-
mary of the more than 200 papers that have 5.3.1 N-substituents. N-demethylation of
appeared on the SAR of cocaine and its analogs cocaine has only a minor effect on affinity at
5 Structure-Activity Relationships

monoamine transporters (161). In phenyl- would suggest that this interaction should be
tropane analogs where the ester linkage has very weak.
been removed (281,extensions of the N-alkyl Replacement of the nitrogen atom with ox-
out to n-butyl have no effect on dopamine ygen as in (30) gives compounds that retain
transporter affinity (162). Effects a t the se- high affinity for the dopamine transporter
rotonin transporter are variable, but affinity (165).This finding was accommodated by pro-
only decreases modestly. At the norepineph- posing that the oxygen atom could act as a
rine transporter, affinity drops