to this view, the duration of receptor occupation determines whether a molecule is an
agonist, partial agonist, or antagonist. Accordingly, the concept of intrinsic activity
becomes unnecessary. The rate theory offers an adequate explanation for the ability of
some antagonists to trigger a response before blocking a receptor, and also accounts for
desensitization. However, it lacks a plausible physicochemical basis and conflicts with
some experimentally established facts (e.g., the slow dissociation rate of agonists).
Theinduced-fit theory, developed by Koshland primarily for enzymes, states that the
morphology of a binding site is not necessarily complementary to the conformation—
even the preferred conformation—of the ligand. According to this theory, binding pro-
duces a mutual plastic molding of both the ligand and the receptor as a dynamic
process. The conformational change triggered by the mutually induced fit in the recep-
tor macromolecule is then translated into the biological effect. Although this model
does not lend itself to the mathematical derivation of binding data, it has altered
our ideas on ligand–receptor binding in a revolutionary way, eliminating the rigid and
obsolete “lock and key” concept of earlier times.
There are other theories of drug–receptor binding relationships. Belleau’s macro-
molecular perturbation theory suggests that when a drug–receptor interaction occurs,
one of two general types of macromolecular perturbation is possible: a specific confor-
mational perturbation leads to a biological response (agonist), whereas a nonspecific
conformational perturbation leads to no biological response (antagonist). Changeux’s
activation–aggregation theoryis an extension of the macromolecular perturbation
theory and suggests that a drug receptor (in the absence of a drug) still exists in an equi-
librium between an activated state (bioactive) and an inactivated state (bio-inactive);
agonists bind to the activated state while antagonists bind to the inactivated state.
Interesting though these theories may be, most are of limited practical use to the med-
icinal chemist who is about to design a drug. To the drug designer, a receptor is a flexi-
ble macromolecule (usually a protein) capable of a dynamic “hand-in-glove” (rather than
“lock-in-key”), geometrically precise, stereospecific interaction with a flexible drug
molecule, mediated via two or more specific intermolecular binding forces; this interac-
tion, in turn, leads to an alteration in some biological or biochemical process. Because
of this latter requirement, the receptor site should be somehow linked to the functional
domain of the protein, so that drug binding may influence protein biological function.
2.6 EXPERIMENTAL QUANTIFICATION OF DRUG–RECEPTOR
BINDING INTERACTIONS
The drug–receptor interaction may be quantified through the use of binding constants,
which are derived from in vivo pharmacological experiments or from the in vitro use of
labeled ligands.
As shown above, in the reaction of a drug with a single population of noninteracting sites,
where
RECEPTORS: STRUCTURE AND PROPERTIES 81