Adenosine receptors as therapeutic targets

Abstract

Modulation of adenosine receptors (ARs) using selective agonists and antagonists is a promising therapeutic strategy for the treatment of diseases and disorders of the cardiovascular, renal and nervous systems, as well as endocrine and pulmonary disorders. Although the development of novel AR ligands has therefore been the focus of much research, so far none has been approved for clinical use, in part owing to the ubiquity of ARs and the consequent possibility of side effects. However, there has been a recent impetus towards novel clinical targets, stimulated by the discovery and elucidation of the roles of the various AR subtypes and adenosine. The A₁, A_2A, A_2B and A₃ are the four known subtypes of adenosine receptors (ARs). All four subtypes are members of the superfamily of G-protein-coupled receptors, and each of these ARs has a unique pharmacological profile, tissue distribution and effector coupling. Classically, AR signalling is thought to occur through inhibition or stimulation of adenylyl cyclase (also known as adenylate cyclase). However, it is now apparent that other pathways, such as phospholipase C, Ca²⁺ and mitogen-activated protein kinases, are also relevant. Modification of adenosine has been the key strategy for discovering AR agonists and the structure–activity relationships of adenosine at ARs have been extensively probed. Highly selective agonists of the different ARs have been designed through both empirical approaches and a semi-rational approach based on molecular modelling.