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Drug-Receptor

Interaction

Dr. Asma El-Zaher


Associate Professor Of Medicinal Chemistry
Dr. Majdi Bakhaitan
Assistant Professor of Medicinal Chemistry
mmbakhaitan@uqu.edu.sa

Introduction:
The vast majority of drugs show a remarkably high
correlation of structure and specificity to produce
pharmacological effects. Experimental evidence
indicates that drugs interact with receptor sites
localized in macromolecules which have protein-like

properties and specific three dimensional shapes.

A minimum three point attachment of a drug to a

receptor site is required.

In most cases a rather specific chemical structure


is required.

Slight changes in the molecular structure of the


drug may drastically change specificity.

Several chemical forces may result in a temporary


binding of the drug to the receptor
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Essentially any bond could be involved with


the drug-receptor interaction.

Covalent bonds would be very tight and

practically irreversible. Since by definition the


drug-receptor interaction is reversible,
covalent bond formation is rather rare except
in a rather toxic situation.
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Since many drugs contain acid or amine


functional groups which are ionized at

physiological pH, ionic bonds are formed by the


attraction of opposite charges in the receptor
site.

Polar-polar interactions as in hydrogen bonding


are a further extension of the attraction of

opposite charges.
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The drug-receptor reaction is essentially an


exchange of the hydrogen bond between a drug
molecule, surrounding water, and the receptor site.

Finally hydrophobic bonds are formed between nonpolar hydrocarbon groups on the drug and those in
the receptor site. These bonds are not very specific
but the interactions do occur to exclude water
molecules.
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Repulsive forces which decrease the stability of


the drug-receptor interaction include repulsion
of like charges and steric hindrance. Steric

hindrance refers to certain 3-dimensional


features where repulsion occurs between electron

clouds, inflexible chemical bonds, or bulky alkyl


groups.
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Definitions of Classical Binding Terms for Drug-Receptor Interactions

An Agonist: is a substance that interacts with a specific


cellular constituent, the receptor, and elicits an observable
Biological response. It may be endogenous or exogenous
substance.

Partial agonists: acts on the same receptor as agonists ,


however, regardless of its dose it cannot produce the same
maximal biological response as a full agonist

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Intrinsic activity: is a proportionality constant of the ability of


the agonist to activate the receptor as compared to the
maximally active compound in the series being studied.

An antagonist: Inhibits the effect of an agonist but has no

biological activity of its own. It may compete on the same


receptor site that the agonist occupies or it may act on

allosteric site.

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An Inverse agonist negative antagonist: it acts


on the same receptor of the agonist yet produces
an inverse effect.

An auto receptor: a macromolecule typically


found in the nerve ending that regulates the
synthesis and/or the release of its own ligand
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Heteroreceptor: is a receptor that regulates


the synthesis and/or the release of
chemical mediators other than its own
ligand.

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Receptor Down-regulation: Is a
phenomenon whereby an agonist , actually
induces a decrease in the number of those
receptors available for binding.
Receptor up-regulation: Is a phenomenon
whereby an agonist , actually induces an
increase in the number of those receptors
available for binding.

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Affinity: is the ability of a drug to combine with a


receptor; it is proportional to the binding
equilibrium constant KD. A ligand of low affinity

requires a higher concentration to produce the


same effect. Both agonists and antagonists have
affinity to the receptor.

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Efficacy: Is a measure of the biochemical or


physiological effect which results, following
the binding of a drug to its target. Efficacy
is a measure of the maximum effect the
drug can produce
Potency: refers to the dose of a drug
required to produce a specific effect of
given magnitude (usually 50% of the
maximum effect) as compared to a standard
reference. Potency is dependent upon both
affinity and efficacy

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Classical Theories of Drug-Receptor Binding Interaction

Occupation Theory: Drugs act on

independent binding sites and activate them,


resulting in a biological response that is
proportional to the amount of drug-receptor
complex formed. The response ceases when
this complex dissociates.

D+R

DR

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Rate theory: the response is proportional to the rate of


drug-Receptor complex formation. According to this

view, the duration of Receptor occupation determines


whether a molecule is agonist, partial agonist of
antagonist.

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The induced-fit theory: States that the morphology of the binding


site is not necessarily complementary with even the preferred
conformation of the ligand. According to this theory, binding
produces a mutual plastic molding of both the ligand and the

receptor as a dynamic process. The conformational change


produced by the mutually induced fit in the receptor

macromolecule is then translated into the biological effect,


eliminating the rigid and obsolete key and lock concept of
earlier times.
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Macromolecular perturbation theory: Suggests that when a drugreceptor interaction occurs, one of two general types of

Macromolecular perturbation is possible: a specific


conformational perturbation leads to a biological response
(agonist), whereas a non specific conformational perturbation
leads to no biologic response (Antagonist).

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Activation-Aggregation theory: is an extension of the


Macromolecular perturbation theory and suggests that a drug
receptor (in the absence of a drug) still exists in an equilibrium
between an activated state (Bioactive) and an inactivated state
(Bio-inactive); agonists bind to the activated state and antagonist
to the inactivated state.

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These models emphasize the fact that many


receptors are not just simple macromolecules,

which interact with a drug in hand in glove


fashion. On the contrary, some receptors are
extremely dynamic, existing as a family of low-

energy conformers existing in equilibrium with


each other.
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Other receptors have complex multi-unit structures, being


composed of more than one protein; facilitatory and
inhibitory interactions exist between these subunits and
may alter the drug-receptor interaction.

Finally some receptors are not only dynamic in terms of


their shape, but also mobile, drifting in the membrane like
an iceberg in the ocean.

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The two-state receptor model : Was developed on the


basis of the kinetics of competitive and allosteric
inhibition as well as through interpretation of the
results of direct binding experiments.

It postulates that a receptor, regardless of the presence

or absence of a ligand, exists in two distinct states: the


R (relaxed, active or on) and T (Tense, inactive or off)
states, which are in equilibrium with each other.
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An agonist (Drug, D) has a high affinity for the R state


and will shift the equilibrium to the right, An antagonist
(Inhibitor, I) will prefer the T state and will stabilize the
TI complex. Partial agonists have about equal affinity
for both forms of the receptor.

In contrast to the classical occupation theory the


agonist in the two-state model does not activate the
receptor but shifts the equilibrium toward the R form.
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Other theories

The receptor cooperativity model

The mobile receptor Model

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Prodrug Drug Latentiation


Prodrug: is inactive drug that is converted to
active drug by metabolic hydrolysis.

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DRUG LATENTIATION:
TYPES

Carrier-Linked Prodrugs

result from a temporary linkage of the active


molecule with a transporter (carrier)
(e.g. bacampicillin)

Bioprecursors
result from an in vivo molecular
modification of the drug itself
(e.g. sulindac, cyclphosphamide)
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Drug

Chemical synthesis

+
Temporary
Transporter
(Carrier)

Regeneration in vivo

Prodrug
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A well-designed carrier-linked prodrug


satisfies the following criteria:
The link between drug and transporter (carrier) is usually a
covalent bond.
The prodrug is usually inactive or less active than the drug.

Link between drug and carrier is broken in vivo.

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A well-designed carrier-linked prodrug


satisfies the following criteria:
The prodrug, and in vivo released carrier, must be nontoxic.

Generation of the drug must take place with rapid


pharmacokinetics to (1) ensure effective drug levels,
and (2) minimize direct prodrug metabolism.

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IN VIVO
METABOLISM

+ CH2=O
+ CH3C(CH3)2COOH

O
CHCNH
NH2
O
AMPICILLIN ( AMPICIN, PENBRITIN)

S
N

Me
Me

+ CO2
+ CH3CHO
+ CH3CH2OH

COOH
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The Active Metabolite Concept

DRUG

ACTIVE METABOLITE

acetanilide

acetaminophen

imipramine

desipramine

L-DOPA

dopamine

phenylbutazone

oxyphenbutazone

chloral hydrate

trichloroethanol

proguanil

cycloguanil
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sulindac
reductive bioactivation
of sulindac

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cholesterol
targetor

spacer

peptide

passive transport through BBB


oxidation

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enzymatic removal of cholesterol

YAGFL

enzymatic release
of peptide

YAGFL
enkephalin
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Prodrug =

Drug Latentiation

Objectives of Prodrug Design:


1. To Absorption & distribution ( bioavailability)
Ex.1 : Dipivaloyl ester of Epinepherine to corneal absorpti
O

OH

OH
O

HO

NHMe
NHMe

HO
O

Dipivaloyl ester

Epinephrine
In vivo
Poor corneal penetration

Good ocular absorption

Dipivaloyl prodrug used for treatment of Glucoma

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Ex.2 : To oral bioavailability of PenicillinG which


can not be orally administered due to its ionizable
COO group.So water solubility by using double
esters

e.g. Pivampicillin & Bacampicillin


Penicillin
S

CCH3
CCH3

COO

CH-O-C-O-C2H5

Bacampicillin

CH3

Me
CH2- O- C C Me
O

Pivampicillin

Me
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Ex.3 : Corticosteroids used for topical absorption by


esterification or acetonidation.

e.g. Fluocinolone acetonide (R = H) & fluocinolone acetate


are prodrugs as topical antiinflammatory
O

CH2

OR

C
Me
HO

CH3
O
O

Me

CH3

acetonide
F

O
F
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2. To Patient Acceptability :

Ex1. to mask the bitter taste of Chloramphenicol by usin


Palmitate ester (insoluble produng).
As Chloramphenicol is highly soluble & bitter
H
OH

OH
CHCl2

N
O

O2N

OH

H
CHCl2

N
O2 N

O
(CH)14CH3
O

ester
Chloramphenicol
( Bitter taste )

Chloramphenicol Pamitate
(without Bitter taste )
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3. To Solve Formulation problems : e.g. Increase solubility

Ex.1 : Prodrug for diazepam


Diazepam itself is water insoluble not suitable for IV inj
The open chain prodrug is water soluble, in vivo amidase enz.

cleaves an amino acid so spontaneous cyclization of the product


active diazepam which go to CNS.
Cl

CH3 O
N
H
N
O

CH3 O
N

R
NH2

HOOC

NH2

Cl

H2N

invivo amidase

Open chain prodrug

CH3 O
N

(Water soluble)

Cl

in

vi v
cy

za
cli

n
tio

Diazepam

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Ex.2 : To improve solubility of chloramphenicol for its


parental use by using aqueous solution of chloramphenica
succinate or phosphate as water soluble
esters & salt
O
CH2-O C

Salt

ester

O
CH2-O

Na+ -O C

P O-Na+
O-Na+

Chloramphenicol Succinate

Chloramphenicol Phosphate

ester + ionizable salt


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Ex.3 : Prednisolone water soluble injectable form


By formation of Phosphate, Succinate or Acetate
ester salt
R-gp.
O
HO

CH2-OH
O

OH
HO

CH2-O-C-CH2CH2COO_Na+
OH
Water soluble

R = - C -CH2-CH2-COO-Na+

Sodium Succinate

O
O

Prednisone

O-Na+

R = -P

Prednisone Sodium Succinate


Disodium Phosphate
ester

O-Na+
O

R = -C-CH3

Acetate ester

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4. To decrease Toxicity ( side effect ) :


the drug is administered in a nontoxic, inactive
form & then slowly converted to the active form.

Ex. : Diglyceride ester of NAPROFEN (NSAID)


CH2O-CO(CH2)11CH3
MeO

CH2-CH-COOH
CH3

Naproxen (Anti-inflammatory)

COO CH
CO-CHO(CH2)11CH3

Diglycerides Ester

With Gastric irritation side effect


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5. To Prolong Duration of

Drug Action ( Prolonged release)

EX. : Haloperidol & Fluphenazine decanoate:

As I.M oil injection last for 1 month as antipsychotic


OR
O
N
Cl

O
Haloperidol : R = H

R=

(CH2)8-CH3

S
N

Decanoate Ester

CF3

CH2 CH2 CH2 N

N CH2 CH2

OR

Fluphenazine: R = H
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6. To avoid drug instability :


e.g. to avoid firstpass metabolism.
EX. : Naltrexone anthranilate or acetyl salicylate esters :
Anthranilate : R =

O
C

HO
O
Acetyl Salicylate: R =

RO

H2N

AcO

C O

PRODRUGS of 45-& 28-fold resp. more effectiv

Naltrexone : (R = H)

It undergoes 1st pass metabolism


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7. For Site specificity = Prodrug for selective distribution


{ DRUG TARGETING }
Ex.1 : Oxyphenisatin
Oxyphenisatin can be taken only rectally.
The acetylated form can be taken orally &
activated only in the intestine.
O
H3 C

HO

O
O

CH3

OH

Terminal ileum
O
N
H

Prodrug for oxyphenisatin


can be taken orally

O
N
H

Active oxyphenisatin
"bowel sterilant"
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Ex.2 : Diethyl stilbesterol Phosphate


Its more selective in the treatment of prostatic
Cancer than DES, as the prostatic cancer tissue
contains high conc. of Phosphatase enzyme,
where DES phosphate is reactivated only at the
site of action
O
P

OH

OH
O
P
HO

OH
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Ex.3 : Progabide : It is a prodrug for gamino butyric acid (GABA


active part

OH

O
N

NH2

O
in Brain

H2N

OH

Schiff's base linkage

Cl

GABA

Progabide

-GABA itself is too hydrophilic and can not cross BBB


-So prodrug increases lipophilicity to cross BBB, once
inside the brain it is hydrolyzed to GABA.
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Ex.4 : Brain-specific delivery :


by Dihydropyridinepyridinium system
By attaching a reversible redox drug delivery system
to the drug cross BBB & Once inside the brain the
carrier is oxidized into a hydrophilic compound to be
kept in the brain which is slowly hydrolyzed to the drug.
O

BBB

C X- Drug
N
N

Me

C X- Drug

C X- Drug

Metabolism

+
N

(Oxidase)

Quaternary ionic form

Me

Me

(locked in brain)

PRODRUG with carrier system


1,4-dihydropyridine- 3-carboxylic acid

Hydrolysis

COOH

Active drug

Lipophilic

+
N

Me
Trigonelline
( nontoxic)

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e.g.1: Brain delivery of GABA (g-Amino butyric acid)

H3N CH2-CH2-CH2-COON
GABA

BBB

C NH CH2-CH2-CH2-COO-C6H11

In vivo Cleavage
{ esterase}

Me

( can not penetrate BBB)


BBB Carrier System

GABA

(Lipophilic)

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e.g.2 : Brain delivery of b-lactam antibiotics :


-For treatment of bacterial meningitis.
-lactams are hydrophilic can not cross BBB by
themselves.
Dihydropyridine carrier to -lactams make them able to
cross BBB. Tri partate prodrug : (( Double ester with
penicillins ))
R
C

H
N

Carrier

CH3
CH3
O

O
N
O

S
Brain

C
X

Oxidation

N
Linker

CH3
CH3

CH3

O
N
C

C
X

N
CH3

Double ester ( Highly lipophilic )


pass BBB

( Highly hydrophilic )
Locked in brain

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Formation of a toxic prodrug


(carrier-mediated) metabolite which
is not produced from the drug.
Consumption of a vital endogenous component
(e.g. glutathione) during metabolic process.

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Generation of a toxic metabolite


from the inert carrier moiety.

Release of an endogenous modifier (causing


enzyme induction, altered drug excretion,
displacement of protein-bound compounds, etc.).

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