2.2 THE NATURE OF RECEPTORS AND CRITERIA
FOR RECEPTOR IDENTITY
From the medicinal chemistry perspective, a receptor is a biological macromolecule
that yields a biological response upon interaction with a drug molecule. True receptors,
that is, those initiating a chain of physicochemical events leading to a pharmacological
response, have a diverse molecular nature. Among the well-described receptors, several
classes of receptor molecules may be distinguished:
- Lipoproteins orglycoproteinsare the macromolecules that most commonly form
receptors. They are often firmly embedded in the plasma membrane or cell-organelle
membrane as intrinsic proteins (see section 7.1). At times, this renders their isolation
and subsequent functional reconstitution difficult, as their structure may be dependent
upon the surrounding membrane. Isolation of such a receptor molecule may cause its
structural collapse, even to the extent that specific binding properties are lost. - Pure proteins are frequent drug receptors, as in the case of enzymes. Many drugs
exert their effects by specifically affecting enzymes involved in vital biochemical
reactions (see section 8.2). - Nucleic acids comprise an important category of drug receptors. A number of antibi-
otics and antitumor agents either interfere directly with DNA replication or tran-
scription, or inhibit translation of the genetic message at the ribosome level. Certain
steroid hormones may also have DNA as their acceptor site (see chapter 8). - Lipidsmay very occasionally be regarded as receptors. Cell membranes contain
“protein icebergs floating in a sea of lipid,” and many drug molecules do interact
with cell membranes. Lipids intimately envelop proteins and thus may profoundly
influence their structure and function. At one point it was believed that non-specific
interactions with lipids were the primary mechanism of action of general anesthet-
ics through perturbation of membrane fluidity; however, this mechanistic hypothe-
sis has now been largely supplanted by the identification of specific interactions of
general anesthetics with GABAergic receptors (see section 8.4).
When one starts to work with a new class of molecules or a new tissue, it is important to
use an extensive set of criteria for receptor identification in both in vitro andin vivo studies.
These criteria are as follows:
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