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MACROMOLECULAR NATURE OF DRUG RECEPTORS
Most receptors are proteins, presumably because the structures of polypeptides provide both the necessary diversity and the necessary specificity of shape and electrical charge. Receptors vary greatly in structure and can be identified in many ways. Traditionally, drug binding was used to identify or purify recep-tors from tissue extracts; consequently, receptors were discovered after the drugs that bind to them. However, advances in molecular biology and genome sequencing have effectively reversed this order. Now receptors are being discovered by predicted structure or sequence homology to other (known) receptors, and drugs that bind to them are developed later using chemical screening meth-ods. This effort has revealed, for many known drugs, a larger diversity of receptors than previously anticipated. It has also iden-tified a number of “orphan” receptors, so-called because their ligands are presently unknown, which may prove to be useful targets for the development of new drugs.The best-characterized drug receptors are regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones. This class of recep-tors mediates the effects of many of the most useful therapeutic agents. The molecular structures and biochemical mechanisms of these regulatory receptors are described in a later section entitled Signaling Mechanisms & Drug Action.
Other classes of proteins that have been clearly identified as drug receptors include enzymes, which may be inhibited (or, less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate); transport proteins (eg, Na+/K+-ATPase, the membrane receptorfor cardioactive digitalis glycosides); and structural proteins (eg, tubulin, the receptor for colchicine, an anti-inflammatory agent).
This sections deals with three aspects of drug receptor function, presented in increasing order of complexity: (1) receptors as deter-minants of the quantitative relation between the concentration of a drug and the pharmacologic response, (2) receptors as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs, and (3) receptors as key deter-minants of the therapeutic and toxic effects of drugs in patients.
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