This document discusses receptor occupancy theory and dose-response curves. It explains that receptor occupancy theory is based on the law of mass action, where response comes from a drug occupying a receptor. A dose-response curve shows the observed effect of a drug as a function of its concentration in the receptor compartment. The curve reaches an asymptotic maximum when all receptor sites are occupied. The drug-receptor interaction is characterized by drug binding to the receptor, followed by a response in the biological system. The affinity of drug binding is governed by chemical forces that cause reversible association with the receptor. This relationship depends on the forward association rate and reverse dissociation rate. At equilibrium, the dissociation constant is the ratio of the off-rate and on

1. Jaineel Dharod
Dept. of Pharmacology

3. » 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

4. » Figure shows a typical dose–response curve; it
reaches a maximal asymptotic value when the drug
occupies all the receptor sites.

5. » 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.

6. » This simple relationship, permits an appreciation
of the reliance of the interaction of drug (D)
with receptor (R) on both the forward
association rate (k1) and the reverse or
dissociation rate (k2).
» At any given time, the concentration of agonist–
receptor complex [DR] is equal to the product of
k1[D][R] minus the product k2[DR].

7. » At equilibrium
When d[DR]/dt = 0,
k1[D][R] = k2[DR].
» The equilibrium dissociation constant (KD) is
then described by ratio of the off-rate and the
on-rate (k2/k1).

8. » The affinity constant (KA) is the reciprocal of the
equilibrium dissociation constant (KD)
» KD = 1/KA
» Thus, A high affinity means a small KD.
» Using this simple model of Equation permits us to
write an expression of the fractional occupancy (f) of
receptors by agonist:

9. » This can be expressed in terms of KA (or KD) and [D]:
» Thus, when [D] = KD, a drug will occupy 50% of the
receptors present. Potent drugs are those which
elicit a response by binding to a critical number of a
particular receptor type at low concentrations (high
affinity) compared with other drugs acting on the
same system and having lower affinity and thus
requiring more drug to bind to the same number of
receptors.

11. A. Competitive antagonism occurs when the agonist A and antagonist I
compete for the same binding site on the receptor. Response curves for
the agonist are shifted to the right in a concentration related manner by
the antagonist such that the EC50 for the agonist increases (e.g., L
versus L’, L’’, and L’’’) with the concentration of the antagonist.

12. B. If the antagonist binds to the same site as the agonist but does so
irreversibly or pseudo-irreversibly (slow dissociation but no covalent bond), it
causes a shift of the dose–response curve to the right, with further depression
of the maximal response.

13. Allosteric effects occur
when the ligand I binds to a
different site on the
receptor to either inhibit
response (see panel C) or
potentiate response (see
panel D).
This effect is saturable;
inhibition reaches a limiting
value when the allosteric site
is fully occupied.