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Inverse, protean, and ligand‐selective agonism: matters of receptor conformation
Author(s) -
KENAKIN TERRY
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.00-0438rev
Subject(s) - agonism , inverse agonist , agonist , receptor , functional selectivity , chemistry , g protein coupled receptor , partial agonist , ligand (biochemistry) , stimulus (psychology) , intrinsic activity , biophysics , neuroscience , pharmacology , biology , biochemistry , psychology , political science , cognitive psychology , politics , law
Concepts regarding the mechanisms by which drugs activate receptors to produce physiological response have progressed beyond considering the re¬ceptor as a simple on‐off switch. Current evidence suggests that the idea that agonists produce only vary¬ing degrees of receptor activation is obsolete and must be reconciled with data to show that agonist efficacy has texture as well as magnitude.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 differ¬ent agonist types.—Kenakin, T. Inverse, protean, and ligand‐selective agonism: matters of receptor confor¬mation. FASEB J. 15, 598‐611 (2001)