Cholinergic and Adrenergic

Drugs
 Transport of Information in
Organism
• Electrically:
Along neurons due to action potential
• Chemically:
- in synaps
- in cell / target organ
 Synaps: Transport of Information:
chemically

Direction of Nerve Impulse

From Müller, 2004, modified

 Neurotransmiter?
• Substances work to deliver chemical stimulus in
nerve system
• Synthesized by pre-synaptic cells and stored in
vesicle (at the edge of synaptic neuron)
• Released, when there is stimulation of neuron
• Excites or inhibits post-synaptic cells
• Enzymatic degraded or re-uptaken by pre-
synaptic cells
• Re-uptake occurs due to pre-synaptic
receptors (auto receptors), the activation of
them leads to inhibition of neurotransmitter
release (feed back mechanism).
 Pre-synaptic receptors
(auto receptors)
• Presynaptic autoreceptors were
discovered in 1971.
• These receptors regulate the release of
noradrenaline, acetylcholine, GABA
serotonin, histamine, glutamate, etc.
Starke, K., Journal of Neurochemistry, 2001, 78, 685 - 693
 Neurotransmiter?
• Depending on the signal substance, sypnaps can
be divided into exciting and inhibiting synaps.

Examples:
• Gycine and γ-aminobutiric acid (GABA) are
inhibiting neurotransmitter (Activation: influx of
chloride ion, hyperpolarization, reduction of
membrane potential, inhibition of excitation)
• Glutamic acid is exciting neurotransmitter, it
causes activation of glutamic receptor: influx of
sodium ion into cell, depolarization, excitation of
neurons
Neurotrasnmitter and Cotransmitter
• Together with classical neurotransmitter, other
neurotransmitters could be released (up to 3
different cotransmitters) those modify
neurotransmitter effects (strengthen or lessen)
e.g.:
• Neurotransmitter:
Acetylcholine, dopamine, L-noradrenaline, L-
adrenaline, serotonin, histamine, GABA, glutamic
acid, glycine
• Co-transmitter:
Somatostatine, cholecystokinine, neurotensine
 Cotransmitter
• A substance, usually a peptide released from
neurons and modifies the actions of the substance
regarded as the primary transmitter.
• For example, vasoactive intestinal peptide is a
cotransmitter with acetylcholine, and neuropeptide Y
performs a similar role with norepinephrine.
Cotransmitters may also have direct effects on target
cells
(Oxford Dictionary of Biochemistry and Molecular Biology © 1997, 2000, 2006
All rights reserved)
http://www.answers.com/topic/cotransmitter#ixzz2h45Dl4Db
 Classical Neurotransmitter
1. Acetylcholine 3. Amino acids
2. Biogenic amines a) GABA (Gama-
a) Catecholamine: Aminobutyric acid)
– Noradrenalin b) Glycin
– Adrenalin c) Asparagin
– Dopamine d) Glutamic acid
b) Serotonin 4. Neuropeptide
c) Histamine E.g. Encephaline
Structure of Neurotransmitters
From Müller, 2004
 Work of Drugs
• Via specific interaction with endogenous
target molecules:
• Protein:
Receptor
Enzyme
Canal ion
Transport protein
• Nucleic acid
 Descrip Type/ Substance Indica-
Acetylcholine Receptor Work (Agonist)
tion Coupling Class tion
Receptors Nicotinic
Muscu- Cation Muscle
Ach. Muscle constraction Narcose
lar channel relaxant
Receptor
Ganglional transmission
Neuro- Cation of impulses in
nal channel sympathicus and
parasympathicus
Parasympa-
Musc. Ach. Inhibition of M-type-K+- thomimetic,
M1 Gq/11
Recept. Channel pasympa-
tholytic
Reduction of heart freq., Parasympa-
inhibition thomimetic,
M2 Gi/0
neurotransmitter release pasympa-
(presynaptic) tholytic
Glau-
coma,
Parasympa-
post
thomimetic
Contraction of smooth opera-
muscles, secretion of tive
M3 Gq/11 glands, inhibition
neurotransmitter release intestine
(presynaptic) atonie,
Pasympa-
spasm,
tholytic
myadriti
cum
Parasympa-
Inhibition of Ca2+ thomimetic,
M4 Gi/0
Channel pasympa-
tholytic
From Müller, 2004 Parasympatho
mimetic,
M5
pasympatholyti
c
 Ach. Receptor
Membrane Receptor:

1. Ligand-controlled ion channel („ionotrop“) (e.g.

nicotinic acetylcholine receptor)
2. G Protein Coupled Receptor („metabotrop“)
(e.g. Muscarinic acetylcholine receptor)
Transport of Signal Penetrating Cell
Membrane (Ach)
Agonist bound to membrane
receptor
• Case A: Receptor = Ion channel (e.g. nicotinic
Ach Receptor)
Quick Receptor (effects in millisecond)
Direct effect: influx or efflux of ions (Na+, K+, Cl-)
Allosteric: binding sites are separate from channel
 Transport of Signal Penetrating Cell
Membrane (Ach.)

• Case B: Receptor bound to effector system (e.g.

muscarinic Ach receptor)
until effects could be observed, seconds to minutes
are needed (via effector cascade).

• Effector system:
Enzymes: a) Adenylate cyclase cAMP
b) Guanylate cyclase cGMP
c) Phospholipase C, IP3, DAG

• Binding: via G protein (protein binds

Guaninnuncleotide)
 Ach Receptor

From Müller, 2004

Nicotinic Ach Reseptor

From Müller, 2004

 Nicotinic Ach Reseptor
From Müller, 2004
Muscarinic Ach Reseptor
From Müller, 2004
 Muscarinic Ach Reseptor

From Müller, 2004

GPCR Family
Neurotransmitter receptors Peptides/peptide hormones
Adenosine (4) Angiotensin (2)
1-Adreneric (4) Bombesin (3)
2-Adreneric (3) Bradykinin (2)
-Adreneric (3) Chemokine-(2)
Dopamine (5) Chemokine-(2)
Glutamate metabotropic (7) Cholecystokinin (2)
Histamine (3) Endothelin (2)
Serotonin (13) Neuropeptide Y (2)
Muscarinic acetylcholine (5) Opioid (3)
Somatostatin (5)
Tachykinin (3)
Agonist:
- Bound to receptor
- Activates receptor
- Triggers effects

Antagonist:
- Bound to receptor
-Does not activate receptor
-Does not trigger effect, but blocks receptor

Partial Agonist:
Agonist that also in high concentration does not trigger
maximal effect of Intrinsic activities.
Intrinsic effect (IA): Agonist: IA = 1, Antagonist: IA = 0,
Agonist partial: 0 < IA < 1
 From Müller, 2004
Central Nerve System
Structure Activity Relationship (SAR)
• Anionic centre of Ach receptor binds
quaternary-N (cation) of Ach molecule
(ionic interaction)
• Binding strength, increases:
R-NH3+< R-NH2R+< R-NHR2+<R-NR3+
Structure Activity Relationship (SAR)
• Ester group, via C-O-C bond or carbonyl
group, interacts with esteratic centre of
Ach receptor (hydrogen bond)
• The distance between –N- with –O- group:
0.5 or 0.7 nm
• When N-Methyl group is replaced by
bulkier group, muscarinic effect decreases,
nicotinic effect increases
Structure Activity Relationship (SAR)
• When acetyl residue is replaced by more
lipophyl group with bigger van der Waals
volume, the compound will work Ach
antagonist
• Work of Ach is based on membrane
permeability (increasing) for small cations:
Na, K, and Cl. Effects: contraction of
muscle, increasing of gland secretion,
decreasing of blood pressure negative
inotropic effects.
 Nicotine
Comparison: Acetylcholine with Nicotine
Nicotine is an agonist on nicotinic acetylcholine receptor

From Müller, 2004

From Müller, 2004
 Pharmacophor Model of Nicotine
4 points model:
• Pharmacophor elements (1) and (2) are nitrogen
atoms
• Pharmacophor elements (3) und (4) are positions on
nAChR-Protein (nicotinic acetylcholine receptor)
optimally interacting positions (1) und (2)
 Synthesis of Nicotine

From Müller, 2004

 Metabolism of Nicotine

From Müller, 2004

Agonist and Antagonist of Ganglion
Nicotinic Ach. Receptor
• A lot of side effects, influence sympatic
and parasympatic nerve system. Not
applied anymore in therapy
• Agonist: Nicotine, tetramethylammonium
bromide (application only in experimental
pharmacology)
• Antagonist: Tetraethylammonium kloride,
Hexametonium bromide
 Antagonist of Nicotinic Ach.
Receptor on Skeletal Muscle
• Application as muscle relaxant
• Compounds: Derivative of Curare Alkaloid
• Classification:
1. Benzylhydroisotetraquinoline
(Tubocurarine)
2. Indol (Toxiferin C)
3. Substituted Steroid base (Vecuronium
Bromide)
From Müller, 2004
From Müller, 2004
From Müller, 2004
 Agonist of Muscarinic Ach.
Receptor
• Direct
• Indirect (Inhibitor of Acetylcholine
esterase)
• Parasympatomimetic
Agonist of post ganglion Ach. Muscarinic
receptor on parasympatic nerve system
 Parasympatomimetic
• Drug that mimics effects caused by
stimulation of parasympatic nerve system:
direct and indirect
• Direct parasympatomimetic:
Drug having high affinity on post ganglion
muscarinic receptor and takes over the
role of acetylcholine as neurotransmitter
 Parasympatomimetic
• Acetylcholine: not stable, seldom applied as
drug, except topical application on eyes
• Carbacol: Ester of carbamic acid with
choline, slowly hydrolyzed by esterase
• Methacoline: not degraded by non specific
esterase, has chirality due to substitution
methyl group, (+)- and (-)-enantiomer (-): has
different hydrolysis rate by esterase.
• Buthanecol: selective work on muscarinic
receptor
 Parasympatomimetic

• Direct Parasympatomimetic:
- (+)-Muscarin: Alkaloid from Amanita
muscaria
- (+)-Pilocarpin: Main Alkaloid of
Pilocarpus jaborandus
- Arecolin: Main Alkaloid of Areca catechu
From Müller, 2004
 Parasympatomimetic
• Indirect Parasympatomimetic: work
mechanism is based on reaction with
acetylcholine esterase enzyme
• Amide of carbamic acid and ester of
phosphoric acid: inhibition of enzyme,
acetylcholine not hydrolyzed
• There are two groups:
- Reversible: Physostigmin group
- Irreversible: Organophosphate
 Indication of Reversible Indirect
Parasympatomimetic
• Atonie of intestine and bladder
• Antidot for intoxication with muscle
relaxant or atropine (Physostigmin)
• Glaukoma
• Myasthenia gravis (Pyridostigmin):
• Morbus Alzheimer (Rivastigmin)
From Müller, 2004
From Müller, 2004
From Müller, 2004
 Indication of Irreversible Indirect
Parasympatomimetic
• As insecticide, chemical weapon,
treatment of glaucoma (limited)
• Long-time Inactivation of AcCh-Esterase
enzyme
• T1/2: several days
From Müller, 2004
From Müller, 2004
 Reactivator of Acetylcholine
Esterase
• Antidot for intoxication with ihibitor
• Pradiloxim
• Obidoxim
From Müller, 2004
From Müller, 2004
Antagonist of Muscarinic Receptor
(Anticholinergic)
• Peripheral work: parasympatic nerve
system, postganglion, ex. On smooth
muscle („neurotrope Spasmolytic“):
Parasympatolitic
• Central work: Blockade of muscarinic
AChR in Brain
Antagonist Work on muscarinic AChR
• Central nerve system: exitation, halusination
• Eye: Mydriasis
• Heart: Increase frequency (after temporary
Bradikardi)
• Lung: reduce secretion
• Gastrointestinaltract: Obstipation
• Bladder: relaxation of muscle
• Skin: reduce production of sweat
 Aplication of mAChR Antagonist
• Central:
- Parkinson
- Travel sickness
- Antidot for intoxication with mAChR agonist (ex.
Organophosphate, Nerve gas)
• Peripheral:
- Mydriasis
- Peptic Ulcer
- Hypersecretion
- Cholic
- Incontinent
- Bronchial Asthma, Bronchitis
 Parkinson
• Degeneration of dopaminergic neuron in
Basalganglion
• Imbalance of Neurotransmitter: Dopamine
decreases, Acetylcholine increases, Glutamate
increases
• Symptoms:
1) Motoric (Bradykinesi, Tremor, Rigor)
2) Vegetative effects (Hypersalivation, Seborrhoe,
sweating)
3) Psychiatric disorder (Depression, Apathie,
senile)
Parkinson
Parkinson
Parkinson
Parkinson
From Müller, 2004
Production of L-[F-18]-F-DOPA
 Teraphy of Morbus Parkinson
Up to now only symptomatic
• L-DOPA combined with pheripheral L- DOPA-
Decarboxylase-Inhibitor
• Dopamin-Agonist
• MAO-B-Inhibitor
• COMT-Inhibitor
• Glutamate-(NMDA-)Antagonist
• Muscarin-Antagonist („Anticholinergic“)
 Metabolism of L-DOPA and Dopamine

From Müller, 2004

 MAO Inhibitor

From Müller, 2004

 COMT Inhibitor

From Müller, 2004

Combination of 3 Compounds

From Müller, 2004

 Anticholinergic

From Müller, 2004

 Anticholinergic

From Müller, 2004

 Anticholinergic

From Müller, 2004

Adrenergic Drug
 From Müller, 2004
Central Nerve System
 Biosynthesis of Adrenalin
O O

HO
OH OH
Oxidation

NH2 NH2
HO HO

L-Tyrosine L-Dopa

Decarboxylation
HO H

HO NH2 HO NH2
Oksidasi

HO
HO
L-Noradrenalin (Norepinefrin)
Dopamine

Methylation

HO H
H
HO N
From Müller, 2004, modified
CH3

HO

L-Adrenalin (Epinefrin)
 HO H R = -CH3, -H
H
HO N
R
Metabolism of
Nor(Adrenalin) HO

L-(Nor)-Adrenalin COMT
MAO

HO H
HO H
HO H H
H3CO N
R

O
HO
HO
3,4-Dihydroxymaldelaldehyde Metanephrin

HO H HO H

HO OH H3CO H

O O
HO HO
3,4-Dihydroxymandelic acid

COMT AD
HO H

H3CO OH

From Müller, 2004, modified

O
HO
 Effects of (Nor)adrenalin

• Vasoconstriction
• Increase of blood pressure
• Increase of heart frequency
• Vasodilatation of coronary blood vessel
• Relaxation of bronchial muscle
• Inhibition of intestinal peristaltic
 Adrenergic Receptors

9 subtypes are already identified

From Müller, 2004

 Drugs Work on Adrenergic
Reseptors

• Sympathomimetic (Agonist)
1. Direct (- and -Sympathomimetics)
2. Indirect (Re-uptake inhibitor)

• Sympatholytic (Antagonist)
1. -Sympatholytic
2. -Blocker
 Indications for Agonist and Antagonist of
Adrenoreceptor
• α-Agonist (α-
Sympathomimetic, periphery
work)
- systemic: as Antihypnotic
(vasoconstriction, increase
of blood pressure)
- local: reduction of edema of
mucous (vasoconstriction)
• α2-Agonist (CNS works)
- as Antihypertensive
• α-Antagonist (α-
Sympatholytic, periphey
work)
- as Antihypertensive
(vasodilatation, reduce blood
pressure)
• -Agonist
• 1-Agonist esp. in heart
• Increase of blood pressure
and heart freq. (Therapy of
Bradicardy), pos. inotrop
• 2-Agonist esp. in
Bronchus, Uterus
• Relaxation of smooth
muscle, Vasodilatation:
Bronchospasmolytic,
Tokolytic
• -Antagonist (-Blocker)
- Antihypertensive
- Therapy of coronary hearth
deseases
 α-Sympathomimetic
Systemic: as Antihypnotic
Local: as Vasoconstrictor on eyes, nose
I. Phenylethylamine-Derivate II. 2-Imidazolin-Derivate
• 1. 4-Hydroxy-Phenylethylamine- Naphazolin Rhinex, Privin u. a.
Derivate
Xylometazolin Olynth, Otriven
Oxedrin (rac.) Sympatol u. v. a.
Liquidum
Oxymetazolin Nasivin u. a.
Oxilofrin((±)erythro) Carnigen
forte Drg., Tropfen Tramazolin Biciron AT, Ellatun,
Rhinospray
• 2. 3-Hydroxy-Phenylamin-
Derivate Tetryzolin Berberil AT, Yxin AT,
Tyzine, Rhinopront u. a.
Norfenefrin (rac.) Novadral,
Energona
Phenylephrin (R(-)) Mydrial AT,
Visadron AT, (also indirectly
work) Vistosan AT
Etilefrin (rac.) Circupon RR,
Effortil u. v. a.
Gepefrin (S(+)) Wintonin (also
indirectly work )
• 3. miscellaneous
Midodrin (rac.) Gutron
 α-Sympathomimetic

From Müller, 2004

 α-Receptorblocker/α-Receptor-
Antagonist/α-Sympatholytic
• Remove the work of physiological agonist on α-
Receptor: Vasodilatation/reduction of blood pressure
• Classification of active substances

1. Ergot-Alkaloids: Hydrogenated Ergot-Alkaloids

2. Imidazoline-Derivate
3. Chinazoline
4. Miscellaneous
Ergot-Alkaloids and partially Hydrogenated Derivate

From Müller, 2004

 LSD: D-lysergic acid diethylamide
• Synthesized by Albert
Hoffmann in 1943 from
lysergic acid as precursor
• Self tested(Selbstversuch)
• Hallucinogenic: at very low
dose (1µg/kg)
• Non selective Agonist
Serotonin receptor (CNS)
• (zum Teil antagonistische
Wirkung an peripheren
Serotonin-Rezeptor-
Subtypen)
 α-Sympatholytic

2. Imidazoline: non selektive(α1/ α2)

• Tolazolin: Priscol® Inj.-Lsg.
3. Chinazoline
- high Selektivity for α1-Receptor
• Prazosin: Minipress®
• Terazosin: Heitrin®
• Doxazosin: Cardular®
• Bunazosin: Andante®
4. Miscellaneous
• Uradipil: Ebrantil®, Alpha-Depressan®
 α-Sympatholytic

From Müller, 2004

 α-Sympatholytic

From Müller, 2004

 β-Blocker
• Important indications:
Angina pectoris (-1)
Arrhythmia (- 1)
Long term therapy after heart infarct (- 1)
Antihypertensive (- 1)
Treatment of Syndromes after termination of alcohol consume
Prevention of Migraine
Hyperthyroidism
Tremor
local: Increase of intra ocular pressure (non selective - Blocker)
 β-Blocker
• Adverse side effects :
Heart failure
Cardiac arrest
Bronkospasms (-2)
 Chronology of β-Blocker

From Müller, 2004

 Structure Avtivity Relationship
HO (R) (R)
R CH3
CH3
HO CH CH2 NH CH CH CH2 NH CH
CH3 OH R
OH
Isoprenalin (I) Tipe Feniletanolamin (II)

HO (R) (S)
CH3
AR O CH2 CH CH2 NH CH
HO CH CH2 NH CH3
OH R
OH
Adrenalin (R-(-)-Efinefrin) Tipe Ariloksi-amino-propanol (III)
Structure Avtivity Relationship
• Cardioselectivity
• ISA (Intrinsic Sympathomimetic Activity)
• Non specific membrane work

Cardiac: mainly beta-1, Bronchial: beta-2.

Selective blockade on beta-1. Blockade on
beta-2 should be prevented (broncospasm !)
 Structure Avtivity
Relationship
• Beta-1 selectivity is achieved by: Acebutolol,
Atenolol, Bisoprolol and Metoprolol. Str.
Similarity: Substitution on position 4 in
benzene ring
• Beta blocker with ISA: Acebutolol, Alprenolol,
Karteolol, Oxprenolol, Pindolol
• Membrane stabilization work: local anestetic:
Acebutolol, Alprenolol, Bupranolol,
Oxprenolol, Propranolol
 Type II β-Bloker
• The first synthesized compound:
Dichlorisoprenalin
• In addition to sympatolytic work, also partial
simpathomimetic, not used in therapy
• Via molecule modification, compounds
without or with very weak ISA activity were
successfully synthesized
• Prototype: Sotalol, Labetolol
 HO Cl
CH3 CH3
HO CH CH2 NH CH Cl CH CH2 NH CH
OH CH3 CH3
OH
Isoprenalin
Diklorisoprenalin

O O CH3
S NH CH CH2 NH CH
H3C OH CH3

Sotalol

O
H2N
CH2 CH2
HO CH CH2 NH CH
OH CH3

Labetalol
 Type III β-Bloker
• Via introduction of –O-CH2- group
between C no. 1 and aromatic group,
type III beta-blocker (propranolol type)
could be obtained
• Essential str.: Aryl ether of 1-Amino-2,3-
propandiol
• Difference criteria: Receptor selectivity,
potency beta receptor blockade,
lipophilisity
 OH
O NH CH3

CH3

Prototipe: Propranolol (Racemat)

OH
O NH CH3
Ar R
CH3

Struktur Esensial, R=H atau CH3

 OH
O NH CH3

H3C CH3
O
Metoprolol
OH
O NH CH3

CH3
O
Betaxolol
OH
O NH CH3
CH3
O CH3
H3C O
Bisoprolol
 OH
O NH CH3
O
CH3
H3C NH
Practolol

OH
O NH CH3
O
CH3 CH3
H3C NH
O
Acebutolol
OH
O NH CH3
O
CH3
H3C

Atenolol
 Stereo selectivity
• Anticlockwise rotating Enantiomers (-)
show stronger pharmacological effects
in comparison to (+)- enantiomers: 50 to
100 X
• Compounds applied in pure
enantiomers: Timolol & Fenbutolol
• Beta-simpatholytic and –
simpathomimetic works depend on
configuration
 Parmacokinetic
• Generally well absorbed (except
Atenolol (50%), Nadolol (20%)
• First Fast Effect in the case of lipophylic
beta-blocker
• Metabolites are not active
References
1. Müller, C., Vorlesung Pharmazeutische Chemie, Bonn -
Wintersemester 2004/05, 2004
2. Roth, H.J., Fenner, H., Pharmazeutische Chemie III -
Arzneistoffe. Struktur – Bioreaktivität Wirkungsbezogene
Eigenschaften. Gustav Fischer-Verlag, 3. Auflage 2000