Allosteric interactions at adenosine A1 and A3 receptors: new insights into the role of small molecules and receptor dimerization. (March 2014)

• Record Type: Journal Article
• Authors: Hill, Stephen J; May, Lauren T; Kellam, Barrie; Woolard, Jeanette
• Is Part Of: British journal of pharmacology. Volume 171:Number 5(2014:Mar.)
• Page Start: 1102
• Page End: 1113
• Publication Date: 2014-03
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12345
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12345-sec-5002" sec-type="section"> <p>The purine nucleoside adenosine is present in all cells in tightly regulated concentrations. It is released under a variety of physiological and pathophysiological conditions to facilitate protection and regeneration of tissues. Adenosine acts via specific GPCRs to either stimulate cyclic AMP formation, as exemplified by G<sub>s</sub>‐protein‐coupled adenosine receptors (A<sub>2A</sub> and A<sub>2B</sub>), or inhibit AC activity, in the case of G<sub>i/o</sub>‐coupled adenosine receptors (A<sub>1</sub> and A<sub>3</sub>). Recent advances in our understanding of GPCR structure have provided insights into the conformational changes that occur during receptor activation following binding of agonists to orthosteric (i.e. at the same binding site as an endogenous modulator) and allosteric regulators to allosteric sites (i.e. at a site that is topographically distinct from the endogenous modulator). Binding of drugs to allosteric sites may lead to changes in affinity or efficacy, and affords considerable potential for increased selectivity in new drug development. Herein, we provide an overview of the properties of selective allosteric regulators of the adenosine A<sub>1</sub> and A<sub>3</sub> receptors, focusing on the impact of receptor dimerization, mechanistic approaches to single‐cell ligand‐binding kinetics and the effects of A<sub>1</sub>‐ and A<sub>3</sub>‐receptor allosteric modulators on <italic>in vivo</italic> pharmacology.</p> </sec> <sec id="bph12345-sec-5001" sec-type="relatedArticles"> <title>Linked Articles</title> <p>This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit <ext-link ext-link-type="doi" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">http://dx.doi.org/10.1111/bph.2014.171.issue‐5</ext-link></p> </sec> </abstract>