THEORIES OF DRUG

RECEPTOR
INTERACTIONS

by Lee Eun Jin

Drug(Ligand) Receptor interaction

Langley (1878)

Drug
Ligand-binding
domain

Drug-Receptor
Complex
k1
k2

Effector domain

Receptor

D+R

k1
k2

Effect
DR

Effect

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 drugreceptor 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 ENZYMESUBSTRATE
INTERACTION
4. MACROMOLECULAR PERTURBAION

 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 drugReceptor 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

compounds exhibit the characteristics they do.

of

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
responseisproportionaltothefractionof
occupiedreceptorsand
theintrinsicactivity
Stephenson responseisaFUNCTIONofoccupancy

maximumresponsecanbeproduced
WITHOUT100%occupation,
i.e.tissueshavesparereceptors
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
full
effect

portion of receptors for

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 receptor type.

 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.

of drug needed to
produce an
effect.
Ligand:
Molecules that binds to a
receptor
Potency:

Amount

Classification of Ligands

a.

agonist

b.

partial agonist

c.

antagonist
pharmacologicalvs.physiologicalvs.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 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

Agonistsdifferinginpotencyandmaximumefficacy

PARTIAL AGONISTS - EFFICACY

Even though drugs may occupy the same # of receptors, the
magnitude
of their effects may differ.

Full Agonist

% Maximal Effect

1.0

Partial agonist

0.8
0.6

Partial agonist

0.4
0.2
0.0
0.01

0.10

1.00

10.00

100.00

[D] (concentration units)

1000.00

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
(Surmountable)
decrease apparent
Potency

NoncompetitiveDecrease apparent
maximum efficacy

Competitive Antagonist
competes with agonist for receptor
with increasing agonist
concentration

surmountable

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