title: Inverse agonism: the classic concept of GPCRs revisited [Review].
abstract: In the classical two-state model, G protein-coupled receptors (GPCRs) are considered to exist in equilibrium between an active and an inactive conformation. Thus, even at the resting state, some subpopulation of GPCRs is in the active state, which underlies the basal activity of the GPCRs. In this review, we discuss inverse agonists, which are defined as GPCR ligands that shift the equilibrium toward the inactive state and thereby suppress the basal activity. Theoretically, if constitutive activation plays an essential role in the pathogenesis of a disease, only inverse agonists, and not neutral antagonists, can reverse this pathophysiological activation. Although many pharmacological examples of inverse agonism have been identified, its clinical importance is still unclear and debated. Thus, even though inverse agonism of angiotensin receptor blockers (ARBs) has been discussed for more than 10 years, its clinical relevance remains to be completely clarified.
authors.affiliation: Department of Endocrinology and Nephrology, The University of Tokyo School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sato
authors.forename: Noriko
authors.initials: N
authors.lastname: Makita
authors.forename: Taroh
authors.initials: T
authors.lastname: Iiri
mesh_terms: D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D054314:Drug Inverse Agonism; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D057911:Angiotensin Receptor Antagonists; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled