antagonists are very similar in structure, but if one considers the relationship between
the endogenous peptide opiates known as enkephalins and the opiate antagonists, the
conspicuous dissimilarity of the two groups is once again apparent.
The most remarkable property of antagonists is their great receptor affinity, which is
sometimes two to four orders of magnitude greater than that of the agonists. Many
antagonists have large nonpolar moieties, usually aromatic rings. Therefore,accessory
binding sitesmust exist on the receptor to accommodate these large hydrophobic
groups. What is even more remarkable is that there are some compounds that are antag-
onistic in more than one system. Diphenhydramine (2.5), for example, has an antihist-
aminic as well as an anticholinergic action.
Competitive antagonists can be viewed in two ways. In one of these, the antagonist
binding site is considered to be topically close to the agonist site and may even partially
overlap it. The antagonist will therefore interfere with agonist access to the receptor,
even though it need not necessarily occupy both the agonist and the accessory sites. On
the other hand, the antagonist may functionally deny agonist accessibility by altering
the receptor affinity. This would be closely analogous to allosteric inhibition.
Allosteric sites are at a distance from the agonist site and may even be on a different
receptor protomer in the receptor–effector complex. Their occupation by allosteric
inhibitors results in a conformational change that is propagated to the agonist site and
changes its affinity. There is thus a mutual exclusion between the agonist and an allosteric
antagonist. Moreover, classical pharmacological models cannot distinguish between com-
petitive and allosteric inhibition. Allosteric effectors are not necessarily inhibitors. Just as
in enzymology, some may activate whereas others deactivate one or another state of a
receptor.
2.7.2 Molecular-Level Conceptual Models of ReceptorsThe transition from classical pharmacological theories of drug–receptor interactions to
real, physical models of receptors is crucial for drug design. As part of this transition,
a number of molecular-level conceptual models of receptors have been put forth over
the years. The two-state receptor modeland the mobile receptor modelare two examples
of such models. Although these models have limited direct utility for the medicinal
chemist involved in drug design, they are extremely instructive for a number of reasons.
These models emphasize the fact that many receptors are not just simple macromole-
cules, which interact with a drug in a “hand-in-glove” fashion. On the contrary, some
receptors are extremely dynamic, existing as a family of low-energy conformers exist-
ing in equilibrium with each other. Other receptors have complex multi-unit structures,
RECEPTORS: STRUCTURE AND PROPERTIES 87