RUCHIT K.

PADODARA
1ST M.PHARM
 INTRODUCTION
 GENERAL CONSIDERATION
 THEORIES OF DRUG-RECEPTOR
INTERACTION
 INTERACTION INVOLVED IN THE
DRUG-RECEPTOR COMPLEX

INTRODUCTION
• When drug is taken, it travels through the body to a target
site and elicits a pharmacological effect. The site of drug
action, which is ultimately responsible for the
pharmacological effect, is a receptor.
• Receptor are mostly membrane-bound proteins that
selectively bind small molecules, referred to as ligands, that
elicit some physiological response.
• Receptors are generally integral proteins that are embedded
in the phospholipid bilayer of cell membranes.
• Drugs do not create new functions. They modify the inherent
functions of the tissues or cell concerned.
• Hence,drug act by stimulating or depressing cellular activity;
replacing deficient substance; causing irritation; or by killing
or weakening the invading foreign organisms.

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

receptor.
 Intrinsic activity:It is the ability of the drug to activate
(induce a conformational change in)the receptor consequent
to receptor occupation.
Agonist:have both affinity and maximal intrinsic activity.
Comoetative antagonist:have affinity but no intrinsic
activity.
Partial agonist:have affinity but submaximal intrinsic
activity.
inverse agonist:have affinity but intrinsic activity with a
minus sign.

GENERAL CONSIDERATION
 The driving force for the drug-receptor interaction can be
considered as a low energy state of the drug-receptor
complex,
 Where kon is the rate constant for formation of the drug-
receptor complex, which depends on the concentration of
the drug and the receptor, and koff is the rate constant for
breakdown of the complex, which depends on the
concentration of the drug-receptor complex as well as other
forces.
 The biological activity of drug is related to its affinity for the
receptor, i.e., the stability of the drug-receptor complex.
 This stability is commonly measured by how difficult is for
the complex to dissociate, which is measured by its kd, the
dissociation constant for the drug-receptor complex at
equilibrium.
 Drug-receptor complex
Koff

INTERACTIONS INVOLVED IN THE DRUG-RECEPTOR

COMPLEX
 The interactions involved in the drug-receptor complex are
the same forces experienced by all interacting organic
molecules and include
1. Covalent bonding
2. Ionic interactions
3. Ion-dipole and dipole-dipole interactions,
4. Hydrogen bonding
5. Charge transfer interactions
6. Hydrophobic interactions, and
7. Van der waals interactions
Drug-receptor interaction involve one or more of the
following types of bonding

Covalent bonding: The stability of this type of bond hardly

permits the formation of an easily reversible drug-receptor
complex.
 Only when the receptor is inactivated by an irreversible
antagonist, there is the formation of covalent bond.
E.g. acetylcholinesterases are irreversibly
inactivated by a number of phosphate esters.

• Ionic interaction: For protein receptors at physipological pH

basic groups such as the amino side chain of arginine,lysine
provide a cationic environment.
• Acidic groups, such as the carboxylic acid side chain of
aspartic and glutamic acid, are deprotonated to give anionic
groups.
• The antidepressent drug pivagabine is used as an example
of molecule of a molecule that can hypothetically participate
in an ionic interaction with an arginine residue.


 I
on-dipole and Dipole-dipole Interaction: As a result of the
greater electronegativity of atoms such as oxygen, nitrogen,
sulfur,and halogen relative to that of carbon, C-X bonds in
drugs and receptors, where X is an elecronegative atom, will
have an asymmetric distribution of elecrons;this produce
electronic dipoles.
 These dipoles in a drug molecule can be attracted by other
dipoles in the receptor, provided charges of opposite sign
are properly alignd.Because the charge of dipole is less than
that of an ion, a dipole-dipole interaction is weaker than an
ion-dipole interation. In figure the insomnia drug
 zaleplon(sonata) is used to demonstrate these interaction.

Hydrogen bonding: An imp. type of bonding between drugs

and receptors is a weak and easily broken H-bond. Since many
drugs contain hydroxyl,amino, carboxyl and carbonyl groups,
they can form H-bonds with the receptors complex
• The reduced potency of many sulfur analogues of oxygen
containing drugs has been attributed to the reduced ability of
sulfur to form H-bond.
• H-bond are a type of dipole-dipole interaction
• The interaction denoted as dotted line –X-H····Y, to indicate
that interaction between H and Y also occurs.

• Charge-Transfer Complexes :When a molecule that is a

good electron donor comes into contact with a molecule that
is a good electron acceptor, the donor may transfer some of
its charge to the acceptor.
• This forms charge transfer complex, which, in effect is
molecular dipole-dipole interaction.
• Electron donor contains π electrons,
• E.g. alkenes, alkynes and aromatic moieties with electron
donating substituents or groups that have a pair of non-
bonded electrons, such as O,N and S moities.
• Acceptor groups contain electron deficient π orbitals.
• E.g. alkenes, alkenes, alkynes and aromatic moieties with
electron withdrawing substituents.

• Hydrophobic Forces In the presence of a non-polar

molecule or region of a molecule, the surrounding water
molecule orient themselves and, therefore, are in a high
energy state than when only the water molecule are around.
• When two nonpolar groups, such as a lipophilic group on a
drug and a nonpolar receptor group, each surrounded by
ordered water molecules become disordered in an attempt to
associate with each other, this increase in entropy,
therefore,result in a the free energy that stabilises the drug-
receptor complex.
• This stabilisation is known as hydrophobic interaction. it is
reversible type of bonding that liberates energy.

• Van der waals or london dispersion forces: Van der

waals bonds exist between all atoms,even those of noble
gases, and are based on polarizability or the induction of
 asymmetry in the electron cloud of an atom by a nucleus of a
neighbouring atom. Such forces operate within an effective
distance of about 0.4 to 0.6 nm and exert an attractive force
of less than 2 kj/mol.
• Threfore, they are often overshadowed by stronger
interactions.
• Example of multiple of drug receptor interaction excluding
van der waal interaction
•

RECEPTOR SITE
THEORIES
A)OCCUPATION THEORY:
 Receptor occupancy theory, in which it is assumed that
response emanates from a receptor occupied by a drug, has
its basis in the law of mass action.
 The basic currency of receptor pharmacology is the dose–
response curve, a depiction of the observed effect of a drug
as a function of its concentration in the receptor
compartment.
 Figure shows a typical dose–response curve; it reaches a
maximal asymptotic value when the drug occupies all the
receptor sites.

 In general, the drug–receptor interaction is characterized first

by binding of drug to receptor and second by generation of a
response in a biological system.
 The first function is governed by the chemical property of
affinity, ruled by the chemical forces that cause the drug to
associate reversibly with the receptor.
 B)RATE THEORY:
• As an alternative to the occupancy theory, Paton proposed
that the activation of receptors is proportional to the total
number of encounters of the drug with its receptor per unit
time.
• Therefore, the rate theory suggest that the pharmacological
activity is a function of the rate of association and
dissociation of the drug with the receptor,and not the number
of occupied receptors.
• Each association would produce a quantum of stimulus. In
the case of agonists, the rate of both association and
dissociation would be fast.
• Where in case of antagonist rate of association would be
fast,but the dissociation would be slow.
C)THE INDUCED-FIT THEORY OF ENZYME-SUBSTRATE
INTERACTION:
• The induced-fit theory of koshland was originally proposed
for the action of substrates and enzymes.
• According to this theory the receptor need not necessarily
exists in the appropriate conformation required to bind the
drug.
• As the drug approches the receptor, a conformation change
in the receptor could be responsible for the initiation of the
biological response.
• According to the induced-fit theory, an agonist would induce
a conformation change and elicit a response,but an
antagonist would bind without a conformational change.
D)MACROMOLECULAR PERTURBAION THEORY:
• According to this theory, Belleau proposed that interaction of
small molecules of drug or a substrate with a macromolecule
may lead either to
• specific conformational perturbation(SCP)-would result in the
specific response of an agonist i.e. the drug would posses
intrinsic activity.
• Non-specific conformational perturbation(NSCP)-
no stimulant response would be obtained and an
antagonist or blocking action may be produced.
• If a drug posses features which contribute to formation of
both, an equilibrium mixture of the two complexes may
result, which would account for a partial stimulant action.
F)TWO STATE MODEL OF RECEPTOR ACTIVATION :
 Proposed by monad-wyman-changeux
 Two-state model of receptor activation proposes that, in the
absence of the natural ligand or agonist, receptor exist in
equilibrium(defined by equilibrium constant L;) between an
active state (R*)which is able to initiate a biological
response, and a resting state(R) , which cannot.
 In the absence of a natural ligand or agonist,the equilibrium
between R* and R define the basal activity of the receptor A
drug can bind to one or both of these conformational states,
according to equlibrium constants kd and k*d for formation of
the drug receptor complex with resting(D·R) and active state
(D·R*) respectively.
 Full agonists alter the equilibrium fully to the active state by
binding to the active state by and causing maximum
response.
 Partial agonist preferentially bind to the active, but not to the
extent that a full agonist does, so maximum response is not
attained.
 Antagonists have equal affinities for both states(ie. have no
effect on the equlibrium or basal activity and therefore,
exhibit neither positive nor negative efficacy).

TYPES OF RECEPTORS

Type 1: ligand-gated ion channels (also known as

ionotropic receptors).
These are membrane proteins with a similar structure to
other ion channels, and incorporate a ligand-binding
(receptor) site, usually in the extracellular domain.
Type 2: G-protein-coupled receptors (GPCRs). These
are also known as metabotropic receptors or 7-
transmembrane-spanning (heptahelical) receptors.
They are membrane receptors that are coupled to
intracellular effector systems via a G-protein. They
constitute the largest family, and include receptors for
many hormones and slow transmitters, for example the
muscarinic acetylcholine receptor , adrenergic receptors
and chemokine receptors

Type 3: kinase-linked and related receptors.

This is a large and heterogeneous group of membrane
receptors responding mainly to protein mediators. They
comprise an extracellular ligand-binding domain linked to
an intracellular domain by a single transmembrane helix.

Type 4: nuclear receptors.

These are receptors that regulate gene transcription. The
term nuclear receptors is something of a misnomer,
because some are actually located in the cytosol and
migrate to the nuclear compartment when a ligand is
present. They include receptors for steroid hormones,
thyroid hormone, and other agents such as retinoic acid
and vitamin D.
REFERENCES
1)Silverman R.B., The Organic Chemistry of
Drug Design and Drug action, Academic
press,2004,2nd Edition,123-143
2)Kadam S.S., Principles of Medicinal
Chemistry, Nirali Prakashan Pune,Volume-2,44-
48
3)Goodman & Gillman, Manual of
pharmacology and therapeutics, Mcgraw hill &
Companies, New Delhi, 25-26
4)Rang H.P. and Dale M.M,Pharmacology,6th
Edition, Elsevier Publisher,2007,29-30