Medicinal Chemistry

multipotential association. However, it is probably true that a recognition site that
operates an ion gate is more permanently associated with the ionophore than is the drug
or hormone receptor that acts through adenylate cyclase or the phosphatidylinositol
system.

2.8 RECEPTOR ACTION: REGULATION,

METABOLISM, AND DYNAMICS

Like all proteins, receptors or receptor subunits are coded by appropriate genes, tran-
scribed to mRNA, translated, and further post-translationally processed in the rough
endoplasmic reticulum. After the receptor protein is packaged in the Golgi apparatus,
various carbohydrates are removed and others are added to the branched oligosaccha-
ride “antenna” structures; this process is referred to as “capping.” The oligosaccharides
of the receptor glycoprotein seem to serve as recognition units necessary for high-affinity
ligand binding, and also as protection from premature proteolytic degradation. The
assembled supramolecular receptor is then inserted into the cell membrane as an
intrinsic protein,that is, one that usually spans the width of the lipid bilayer. It can
therefore communicate with the extracellular space as well as with the inside of the cell,
thus fulfilling its role as a transmembrane signal transducer.
Membrane-bound receptors undergo dynamic processes that serve as regulatory
mechanisms. This has led to the idea that such receptor regulation is just as important
in the overall response of the system as is the response of the target organ (e.g., a
muscle cell or secretory cell). There are several categories of regulatory mechanisms,
and they differ primarily in the rate of response: some are very fast (milliseconds to
seconds), whereas others are much slower and delayed. At this point, we know of the
following mechanisms:

1. Regulation at the genetic level


2. Regulation by ligand


3. Covalent modification


4. Noncovalent modification


5. Receptor clustering


6. Migration of receptors and receptor internalization


7. Internalization and proteolytic degradation

2.8.1 Receptor Regulation at the Genetic Level

Regulation at the genetic level is often observed for hormones that can regulate the rate
of synthesis either of their own receptor or of other functionally related receptors (e.g.,
regulation of oxytocin receptor synthesis in the uterus by estrogens).

2.8.2 Receptor Regulation by Ligand

Ligand regulation of receptors can be either self-regulatory (homospecific) or trans-
regulatory (heterospecific). In the first case, ligand binding may initiate internalization of
the ligand–receptor complex, thus removing receptors from the cell surface and decreasing

90 MEDICINAL CHEMISTRY