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Department of Receptor Biochemistry, Glaxo SmithKline Research and Development, Research Triangle Park, North Carolina 27709, USA
1Correspondence: Department of Receptor Biochemistry, GlaxoWellcome Research and Development, 5 Moore Dr., Research Triangle Park, NC 27709, USA. E-mail: tpk1348{at}glaxo.com
Concepts regarding the mechanisms by which drugs activate receptors to produce physiological response have progressed beyond considering the receptor as a simple on-off switch. Current evidence suggests that the idea that agonists produce only varying degrees of receptor activation is obsolete and must be reconciled with data to show that agonist efficacy has texture as well as magnitude. Thus, agonists can block system constitutive response (inverse agonists), behave as positive and inverse agonists on the same receptor (protean agonists), and differ in the stimulus pattern they produce in physiological systems (ligand-selective agonists). The molecular mechanism for this seemingly diverse array of activities is the same, namely, the selective microaffinity of ligands for different conformational states of the receptor. This paper reviews evidence for the existence of the various types of agonism and the potential therapeutic utility of different agonist types.—Kenakin, T. Inverse, protean, and ligand-selective agonism: matters of receptor conformation.
Key Words: G-protein-coupled receptors • receptor activation • inverse agonism • receptor theory • constitutive receptor activity
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