DRUG RECEPTOR INTERACTION

Setyo Purwono
Dept Farmakologi & Terapi FK-KMK UGM
 PHARMACODYNAMIC CONCEPTS
 The effects of most drugs result from their interaction with macromolecular
components of the organism.
 These interactions alter the function of the pertinent component and initiate the
biochemical and physiological changes that are characteristic of the response to the
drug.
 The term drug receptor or drug target denotes the cellular macromolecule or
macromolecular complex with which the drug interacts to elicit a cellular response,
i.e., a change in cell function.
 Drugs commonly alter the rate or magnitude of an intrinsic cellular response rather
than create new responses.
Three Dimensional characteristics
 Size : permit binding to its receptor
 Sterochemical orientation
 physical- and electrochemical properties
 Drug-Receptor Theory
1. The occupancy theory
2. The rate theory
3. The induced-fit theory
4. The macromolecular pertubation theory: (induced fit + rate
theory)
5. The activation -agregation theory
Occupancy Theory
 Drug and receptor interact with each other
 When a drug (D) combines with a receptor (R), it does so at a rate which is
dependent on the concentration of the drug and the concentration of the receptor
 The more receptors sites occupied by ligand, the stronger responce

D = drug
R = receptor,
DR = drug-receptor complex
k1 = rate for association and
k2 = rate for dissociation.
KD = Dissociation Constant
KA = Association Constant
Assumptions are made for this equation :
 The interaction is reversible.
 The receptor, ligand, and ligand-receptor complex are in equilibrium.
 The receptor contains one binding site for the ligand.
 The ligand and receptor interact rapidly to form the ligand receptor
complex.
 Equilibrium is reached when the rate at which
ligand-receptor complexes are formed and dissociate are
equal.
 Rate Theory
 Stimulant/ ligand activity is proportional to the rate of drug-receptor combination
rather than the number of occupied receptors
 Stimulant / ligand activity is the result of a series of rapid association and
dissociation of the drug and the receptor
 The number of drug-receptor interaction per unit time determines the intensity of
the response

Macromolecular perturbation theory

Small molecule binding produces in a macromolecule:
Specific conformational perturbations
 Induced-fit theory of enzyme-substrate interaction
 Substrate or drug binding to the receptor induces 3 dimensional conformational
changes in the macromolecule positioning catalytic groups in the correct position to
conduct productive chemistry or altering membrane behavior (e.g. opens channels for
calcium)
 How do we measure or quantify a drug-receptor interaction
Dose-response curve

Dose % contraction Contraction of muscle produced by a

drug
(mg) Emax

0.1 10 100

% contraction
0.3 20 75

1 50 50
3 70
25
10 100
0
30 100 1 3 10 30
EC50 Dose of drug (mg)
 Arithmetic vs. log scale of dose - which one is better?
Contraction of muscle produced by a Contraction of muscle produced by a
drug drug

100 100

% contraction
% contraction 75 75

50 Arithmetic scale 50

Log scale
25 25

0 0
1 3 10 30 0.1 0.3 1 3 10 30
Dose of drug (mg) Dose of drug (mg)

• Rate of change is rapid at first and • Transforms hyperbolic curve to a

becomes progressively smaller as sigmoid (almost a straight line)
the dose is increased • Compresses dose scale
• Eventually, increments in dose • Proportionate doses occur at equal
produce no further change in effect intervals
i.e., maximal effect for that drug is • Straightens line
obtained
• Easier to analyze mathematically
• Difficult to analyze mathematically
 EC50 – dose or concentration of a drug that produces
50% of maximal (half maximal) response

 Emax – maximal effect produced by a drug. It is a

measure of efficacy of a drug

 Efficacy (or Intrinsic Activity) – ability of a bound

drug to change the receptor in a way that produces an
effect; some drugs possess affinity but NOT efficacy

 Kd – concentration of a drug that occupies 50% of the

total number of receptors at equilibrium
2 properties of a drug that determine the nature of its pharmacological effect
# Affinity: refers to how well or avidly a drug binds to its receptor.
Is determined by the Kd or Ka of the drug
# Intrinsic activity (IA) or efficacy refers to the magnitude of
effect the drug has once bound.
IA takes a value between 0 and 1, although inverse
agonists can have an IA between -1 and 0
Type of drugs-receptor interaction !
 Agonist: has significant receptor affinity and full intrinsic activity
(IA = 1)
 Antagonist: significant receptor affinity but no intrinsic activity (IA
= 0)
 Partial agonist: significant receptor affinity but only fractional
intrinsic activity (0<IA<IA)