Medicinal Chemistry

the number of available receptors (as in the case of the insulin receptor). Heterospecific
regulation is shown, for instance, by histamine, which at high concentrations can acti-
vate acetylcholine receptors; and by benzodiazepine anxiolytics (tranquilizers), which
regulate GABA receptors.

2.8.3 Covalent Modification of Receptors

Covalent modification of receptors occurs by phosphorylation, sulfhydryl–disulfide redox
reactions, and proteolytic cleavage, in the same manner as occurs for many enzymes.
Upon ligand binding, the receptor may phosphorylate itself on a tyrosine or serine residue,
or the ligand-induced conformational change may make the receptor a substrate for a
phosphorylase kinase. Sulfhydryl redox reactions, seen in the nicotinic cholinoceptor,
result in alteration of relative ligand sensitivities; in the insulin receptor, they lead to
affinity changes. Thus covalent modifications of receptors, whether homospecific or
heterospecific, lend biochemical significance to the pharmacological terms affinity and
intrinsic activity.

2.8.4 Noncovalent Modification of Receptors

Noncovalent modifications of receptors can involve interactions with small ligands
(ions, nucleotides) or macromolecules (as in the mobile receptor model), leading to
allosteric changes. They can also influence the receptor environment, causing a change
in membrane potential or receptor distribution (clustering, patching). A notable example
is the effect of Na+ions on the relative affinity of opiate receptors toward agonists and
antagonists. The lateral mobility of the ligand–receptor complex, a phenomenon still
not well understood, is further regulated by an alteration in membrane fluidity triggered
by the ligand–receptor complex itself.

2.8.5 Receptor Clustering

Receptor clustering, although a noncovalent interaction, is really an entirely separate
regulatory mechanism. Peptide hormone receptors in particular are known to form clus-
ters that are observable microscopically by use of fluorescent receptor probes. Clustering
is a necessary but insufficient prerequisite for the pharmacological effect. Ligand bind-
ing to clustered receptors is still necessary for cell activation in such instances as insulin
receptor-mediated lipolysis in adipocytes (fat cells). As implied earlier, clustering could
explain receptor cooperativity in a positive sense, as well as in a negative sense.

2.8.6 Receptor Internalization

Receptor clustering also accounts for receptor internalization. The basis of this
phenomenon is endocytosis via coated pits. These pits are apparent in electron micro-
graphs as membrane invaginations coated on the inner (cytoplasmic) side with a web of
the protein clathrine. It has been suggested that certain receptor proteins have structural
domains that allow them to react with coated pits. Receptor clusters in coated pits are
rapidly endocytosed, resulting in the formation of vesicles (endosomes) that are then

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