THEORIES OF DRUG RECEPTOR

INTERACTIONS

by Lee Eun Jin

Drug(Ligand) ↔ Receptor interaction
Langley (1878)

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.
 INTERACTIONS 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 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
6. TWO STATE MODEL OF RECEPTOR ACTIVATION
Other theories
The receptor cooperativity model
The mobile receptor Model
 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 occupie
d
Does not rationalize how two drugs can occupy
the same receptor and act differently
 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.
 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
 Macromolecular perturbation theory:
• Suggests that when a drug-receptor
interaction occurs, one of two general types
of Macromolecular perturbation is possible:
• a specific conformational perturbationleads to
a biological response (agonist),
• whereas a non specific conformational
perturbation leads to no biologic response
(Antagonist
 Ariens
response is proportional to the fraction of occupied receptors and
the intrinsic activity
Stephenson response is a FUNCTION of occupancy
 maximum response can be produced WITHOUT 100% occupation,
i.e. tissues have spare receptors
Receptors are said to be sparespare for a given pharmacological
response when the maximal response can be elicited by an agonist at a
concentration that does not result in occupancy of the full complement
of available receptors
Spare receptors   More receptors available than needed
to elicit maximum response
 allow maximal response without total           receptor occupancy – 
increase sensitivity of the system
 Agonist has to bind only a portion of receptors for full effect
 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
 Activation-Aggregation Theory

Receptor is always in a state of dynamic

equilibrium between activated form (Ro)
and inactive form (To).
 THE TWO-STATE (MULTISTATE) RECEPTOR MODEL
• Was developed on the basis of the kinetics of competitive and
allostericinhibition 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.

Molecular level conceptual model of Receptor

• 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.
• Other receptors have complex multi-unit structures, being composed of
more than one protein; facilitatoryand inhibitory interactions exist
between these subunits and may alter the drug-receptor interaction.
• Some receptors are not only dynamic in terms of their shape, but also
mobile, drifting in the membrane like an iceberg in the ocean.
Two-state (Multi-state) Receptor
Model
• R and R* are in equilibrium
(equilibrium constant L), which
defines the basal activity of the
receptor.
• Full agonists bind only to R*
• Partial agonists bind preferentially
to R*
• Full inverse agonists bind only to R
• Partial inverse agonists bind
preferentially to R
• Antagonists have equal affinities
for both R and R* (no effect on
• basal activity)
• In the multi-state model there is
more than one R state to account
for variable agonist and inverse
agonist behavior for the same
• 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 Rform.
 Terminologies regarding drug
receptor interaction
 Affinity

 Efficacy

 Potency

 Ligand
Affinity: measure of propensity of a drug to
bind receptor; the attractiveness
of drug and receptor

Efficacy: Potential maximum

therapeutic response that a
drug can produce.

Potency: Amount of drug needed to produce

an effect.
Ligand: Molecules that binds to a receptor
 Classification of Ligands 
a.     agonist 
b.     partial agonist
c.     antagonist 
        
pharmacological vs. physiological vs. che
mical 
        pharmacological antagonists 
             - competitive 
                      surmountable 
            - noncompetitive 
 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

endocytosis or degradatio
 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
Agonists differing in potency and maximum efficacy
 PARTIAL AGONISTS - EFFICACY
Even though drugs may occupy the same # of receptors, the magnitude
of their effects may differ.

1.0
Full Agonist
% Maximal Effect

0.8 Partial agonist

0.6
Partial agonist
0.4

0.2

0.0
0.01 0.10 1.00 10.00 100.00 1000.00

[D] (concentration units)
 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
 Types of Antagonists
Competitive Noncompetitive- Decrease
(Surmountable) apparent maximum efficacy
decrease apparent Potency
 Competitive Antagonist

competes with agonist for receptor

with increasing agonist

surmountable
concentration

displaces agonist dose response curve to

the right (dextral shift)

Only affinity, no efficacy

 Noncompetitive Antagonist

drug binds to receptor and stays bound

irreversible – does not let go of receptor

produces slight dextral shift in the agonist DR curve in the

low concentration range

but, as more and more receptors are bound (and essentially

destroyed),
the agonist drug becomes incapable of eliciting a maximal
effect
AGONIST VS ANTAGONIST
Increasing agonist
concentration
 Increasing agonist
concentration higher
Non competitive antagonist affect
receptor function