precise molecular pictures of receptor structure. The reshaping of our ideas on drug
receptors is an ongoing process.
2.7.1 Functional Molecular Properties of Drug ReceptorsEarly receptor models, based on pharmacological data rather than direct ligand-binding
measurements,postulated that agonists and their competitive antagonists became bound
to the same receptor site and competed for it. This view was partly based on findings in
enzymology, in which this concept is generally valid for metabolite–antimetabolite
competition as well as for activity studies of vitamins and hormones. An antimetabolite
is a molecular analog of an intermediate in a physiologically relevant metabolic path-
way that replaces a natural substrate. In doing so, it prevents the biosynthesis of phys-
iologically important substances within the organism. The close structural resemblance
of agonists and antagonists in these categories constitutes direct proof that they have
identical binding sites. The lack of structural correlations between many neurotrans-
mitters and their blocking agents, however, initiated a review of the competitive bind-
ing hypothesis.
It is generally accepted that there is complementarity between a ligand (either
endogenous [e.g., hormone or neurotransmitter] or exogenous [e.g., drug molecule])
and its receptor site in the sense of the induced-fit concept; this suggests a mutual mold-
ing of the drug and macromolecule to take full advantage of stereoelectronic interac-
tions. Under optimal conditions, the energies liberated in binding can reach 40–50
kJ/mol, a figure equivalent to binding equilibrium constants of about 10–8–10–9, which
is considered to represent a high affinity.
Complementarity in the context of induced fit implies a plasticity of the receptor
macromolecule in terms of an ability to undergo conformational changes and associate
with ligands. In its activated state (i.e., a different conformation), the receptor can inter-
act with effector molecules, which then transmit a nerve impulse or other signals to
other structures. The complementarity also determines the selectivity of the receptor.
For stereospecific binding, it is generally assumed that a ligand must have three unequal
substituents; this is considered sufficient for great selectivity. The discrete forms of a
receptor site are, of course, the result of receptor plasticity.
Recognizing this capacity of the receptor to assume different molecular geometries
without a significant change in function is probably essential to achieving some under-
standing of the pluralistic nature of many receptors. It is physiologically and struc-
turally unreasonable to assume that a given type of receptor—probably a complex,
multisubunit structure that is part of an even more complex membrane framework—is
absolutely identical throughout an organism. Mautner pointed out in 1967, long before
the structure of any drug receptor was known in any detail, that the medicinal chemist
would have to deal with an isoreceptor concept in the same matter-of-fact way that
an enzymologist accepts isozymes. Despite recent advances in molecular biology, our
present knowledge of receptor structure is still evolving.
This confusion is complicated even further by receptor multiplicity. Consider, for
example, the presence of opiate receptors in both the central nervous system and the ileum.
Not only do they have different roles as participants in neuromodulation and peristaltic
RECEPTORS: STRUCTURE AND PROPERTIES 85