There are also partial agonists that act on the same receptor as other agonists in a
group of ligands (binding molecules) or drugs. However, regardless of their dose, they
cannot produce the same maximal biological response as a full agonist. This behavior
necessitates introducing the concept of intrinsic activity of an agonist. This is defined
as a proportionality constant of the ability of the agonist to activate the receptor as com-
pared to the maximally active compound in the series being studied. The intrinsic activ-
ity is a maximum of unity for full agonists and a minimum of zero for antagonists. The
intrinsic activity is comparable to the Kmof enzymes.
Anantagonist inhibits the effect of an agonist but has no biological activity of its own
in that particular system. It may compete for the same receptor site that the agonist
occupies, or it may act on an allosteric site, which is different from the drug–receptor
site. In allosteric inhibition, antagonist binding distorts the receptor, preventing the ago-
nist from binding to it; that is, the antagonist changes the affinity of the receptor for the
agonist. In a different system, it may have an independent pharmacological activity.
Aninverse agonist is a drug which acts at the same receptor as an agonist yet produces an
opposite effect. Inverse agonists are also sometimes called negative antagonists. However, an
inverse agonist must be differentiated from an antagonist. Inverse agonists produce biologi-
cal effects opposite to those of agonists; antagonists produce no biological effect.
Anautoreceptor(a macromolecule typically found in a nerve ending) is a receptor
that regulates, via either positive or negative feedback processes, the synthesis and/or
release of its own physiological ligand. Thus, a neurotransmitter receptor may, upon
binding with the neurotransmitter, either increase or decrease the biosynthesis of that
neurotransmitter. This is distinct from a heteroreceptor, which is a receptor that regu-
lates the synthesis and/or release of chemical mediators other than its own ligand.
Receptordown-regulation is a phenomenon whereby an agonist, after binding to a
receptor, actually induces a decrease in the number of those receptors available for bind-
ing. Receptor up-regulation is the opposite and involves an agonist-induced increase in
the number of receptors.
Affinity is the ability of a drug to combine with a receptor; it is proportional to the
binding equilibrium constant KD.A ligand of low affinity requires a higher concentra-
tion to produce the same effect as a ligand of high affinity. Both agonists and antago-
nists have affinity for the receptor.
Efficacydescribes the relative intensity with which agonists vary in the response they
produce when occupying the same number of receptors and with the same affinity. Efficacy
and intrinsic activity are different concepts.
76 MEDICINAL CHEMISTRY
Figure 2.2 A dose-response curve on a semilogarithmic scale.