THEORIES OF DRUG RECEPTOR

INTERACTIONS

by Lee Eun Jin

Drug(Ligand)  Receptor interaction

Drug Drug-Receptor
Complex
Ligand-binding
domain k1

Effector domain k2
Receptor
Effect

k1
D+R DR Effect
k2
 FORCES INVOLVED IN BINDING OF DRUGS TO RECEPTORS.
• 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
• 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.
 FORCES INVOLVED IN THE DRUG-RECEPTOR COMPLEX

• Covalent bonding
• Ionic interactions
• Ion-dipole and dipole-dipole interactions,
• Hydrogen bonding
• Charge transfer interactions
• Hydrophobic interactions, and
• Van der waals interactions
 Development of Drug-receptor theory

• a. Langley(1878): Intercounter of atropine with

pilocarpine in salivary excretion.
• b. Langley(1906):Intercounter tubocurarine with
nicotine in skeletal muscle – “receptive substance”
• c. Ehrlich(1908): “lock and key (receptor)”
• d. Clark(1926-33): Acetylcholine on heart
contraction.
• e. Dale, Ahlquist, Gaddum, Schild, Sutherland, et al.
• Receptor theory was propounded by Alfred Joseph Clark, a
theory of drug action based on occupation of receptors by
specific drugs and the cellular function can be altered by
interaction of the receptors with the drugs.
• The interaction between the drug (D) and receptor (R) is
governed by the Law of mass action; the rate at which new
DR complexes are formed is proportional to the
concentration of D.
• This equation is derived from Langmuir absorption isotherm,
the interaction of drug (D) with receptor (R) on forward or
association rate constant (k1) and the reverse or dissociation
(k2).
• It has been accepted that occupation of the receptor is
essential but itself not sufficient to elicit a response; the
agonist must be able to induce conformational change in the
receptor.
THEORIES OF DRUG RECEPTOR INTERACTIONS

1. OCCUPATION THEORY:
2. RATE THEORY
3. THE INDUCED-FIT THEORY OF ENZYME-SUBSTRATE
INTERACTION
4. MACROMOLECULAR PERTURBAION THEORY
5. ACTIVATION-AGGREGATION THEORY / TWO STATE MODEL OF
RECEPTOR ACTIVATION
Other theories
The receptor cooperativity model
The mobile receptor Model
I. Occupation theory (1926)
* 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.

* Intensity of pharmacological effect is directly proportional to

number of receptors occupied

D + R  DR  RESPONSE

*Response is proportional to the fraction of occupied

receptors
Maximal response occurs when all the receptors are occupied
Does not rationalize how two drugs can occupy
the same receptor and act differently
II. Rate theory (1961)
• The response is proportional to the rate of drug-Receptor
complex formation.

• Activation of receptors is proportional to the total number of

encounters of a drug with its receptor per unit time.

• According to this view, the duration of Receptor occupation

determines whether a molecule is agonist, partial agonist of
antagonist.

• Does not rationalize why different types of compounds

exhibit the characteristics they do.
III. THE INDUCED-FIT THEORY: (1958)
• 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 ligandand 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
• Agonist induces conformational change – response
• Antagonist does not induce conformational change – no
response
• Partial agonist induces partial conformational change -
partial response
IV. Macromolecular perturbation theory
(induced fit + rate theory):
• Suggests that when a drug-receptor
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)
V.Activation-Aggregation Theory
 Monad, Wyman, Changeux (1965) Karlin (1967)
is an extension of the Macromolecular
perturbation theory
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
Receptor is always in a state of dynamic equilibrium
between activated form (Ro) and inactive form (To).

In contrast to the classical occupation theory the ago

nist in the two-state model does not activate the recep
tor but shifts the equilibrium toward the R form.
Drug  Receptor interaction
- Primary way for drug to produce an action

Targets of drug action

 non-specific
 receptors
neurotransmitters
hormones
 enzymes
 transport systems
• ion channels
• active transporters, e.g. uptake blockers
DESENSITIZATION OF RECEPTORS

- Receptor structure change

- Receptor inactivation
(protein inhibitors,
modifications)

- Down regulation of
receptor by
endocytosis or
degradation
 Receptor “agonist”
 Any drug that binds to a receptor and stimulates
the functional activities
 e.g.: adrenaline (epinephrine)

Receptor
Effect

Epinephrine

Cell
 Agonist

Drugs that cause a response

Drugs that interact with and activate receptors;
They possess both affinity and efficacy
Types
Full agonists
An agonist with maximal efficacy (response)
 has affinity plus intrinsic activity
Partial agonists
An agonist with less then maximal efficacy
 has affinity and less intrinsic activity
 Receptor antagonist
 Any drug which can influence a receptor and
produce no response
 e.g.: propranolol (a beta blocker)

propranolol

epinephrine

 Competitive Antagonist: both the drug and its antagonist compete for the same site of the receptor
 Non-competitive Antagonist: the drug and its antagonist do not compete for the same site
 Antagonist
 Interact with the receptor
 Have affinity but NO efficacy
 Block the action of other drugs
 Effect only observed in presence of
agonist