GPCRs as therapeutic targets: a view on adenosine receptors structure and functions, and molecular modeling support

Abstract

G-protein-coupled receptors (GPCRs) represent the largest known family of signal-transducing proteins and transmit signals for light and many extracellular regulatory molecules. GPCRs are dysfunctional or dysregulated in several human diseases and are estimated to be the targets of ~40% of the drugs used in clinical medicine today. Receptors for adenosine belong to this family, and so far four subtypes, the A 1 , A 2A , A 2B , and A 3 , have been recognized. The activation of adenosine receptors (ARs) is largely responsible for the variety of effects produced by adenosine throughout several organ systems. Based on the wide (and often beneficial) effects attributed to the accumulation of endogenously released adenosine, it has long been considered that regulation of ARs has considerable therapeutic potential. In this review, we focus on recent work on adenosine receptors as therapeutic targets and, in particular, on molecular modelling support to adenosine receptors targeting.

Discovery of Novel Benzo[4,5]imidazo[1,2-a]pyrazin-1-amine-3-amide-one Derivatives as Anticancer Human A2A Adenosine Receptor Antagonists

“…The endonucleoside adenosine modulates a wide range of physiological and pathological processes through the activation of adenosine receptors, which belong to a superfamily of G-protein-coupled receptors (GPCR) and can be subdivided into four subtypes A 2A , A 2B , A 1 , and A 3 . The A 2A adenosine receptor (A 2A AR) increases adenylate cyclase activity and levels of intracellular second messenger 3′,5′-cyclic adenosine monophosphate (cAMP), which triggers a series of cellular events .…”

“…The endonucleoside adenosine modulates a wide range of physiological and pathological processes through the activation of adenosine receptors, which belong to a superfamily of Gprotein-coupled receptors (GPCR) 1 and can be subdivided into four subtypes A 2A , A 2B , A 1 , and A 3 . 2 The A 2A adenosine receptor (A 2A AR) increases adenylate cyclase activity and levels of intracellular second messenger 3′,5′-cyclic adenosine monophosphate (cAMP), 3 which triggers a series of cellular events. 4 In the human body, the A 2A AR is ubiquitous and expressed in a variety of organs and tissues, such as the heart, lung, liver, neutrophil, leukocyte, and endothelial cells, implying its role in the regulation of inflammatory and immune responses.…”

N6-Methoxy-2-alkynyladenosine Derivatives as Highly Potent and Selective Ligands at the Human A3 Adenosine Receptor

“…Ado a is involved in the regulation of many physiological and pathophysiological processes through the activation of four cell membrane receptors, termed A 1 , A 2A , A 2B , and A 3 , which belong to the family of G-protein coupled receptors and are ubiquitously expressed in the body. − In particular, the A 3 receptor is negatively coupled to adenylyl cyclase and positively coupled to phospholipase C, resulting in an increase of intracellular Ca ++ levels. , Although the physiological role of the A 3 receptor subtype is not fully understood yet, it has recently attracted considerable interest as a novel drug target . In particular, it has been suggested that A 3 receptor agonists may have potential as cardioprotective , and cerebroprotective agents.…”