Molecular probes for the human adenosine receptors
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REVIEW ARTICLE
Molecular probes for the human adenosine receptors Xue Yang 1 & Laura H. Heitman 1 & Adriaan P. IJzerman 1 & Daan van der Es 1 Received: 23 April 2020 / Accepted: 1 November 2020 # The Author(s) 2020
Abstract Adenosine receptors, G protein–coupled receptors (GPCRs) that are activated by the endogenous ligand adenosine, have been considered potential therapeutic targets in several disorders. To date however, only very few adenosine receptor modulators have made it to the market. Increased understanding of these receptors is required to improve the success rate of adenosine receptor drug discovery. To improve our understanding of receptor structure and function, over the past decades, a diverse array of molecular probes has been developed and applied. These probes, including radioactive or fluorescent moieties, have proven invaluable in GPCR research in general. Specifically for adenosine receptors, the development and application of covalent or reversible probes, whether radiolabeled or fluorescent, have been instrumental in the discovery of new chemical entities, the characterization and interrogation of adenosine receptor subtypes, and the study of adenosine receptor behavior in physiological and pathophysiological conditions. This review summarizes these applications, and also serves as an invitation to walk another mile to further improve probe characteristics and develop additional tags that allow the investigation of adenosine receptors and other GPCRs in even finer detail. Keywords Probes . Adenosine receptors . GPCR . Chemical biology . Radioligands . PET ligands . Fluorescent ligands . Covalent ligands
Introduction Adenosine receptors (ARs) belong to the class A family of G protein–coupled receptors (GPCRs) and are activated by their endogenous ligand adenosine. These receptors have been considered potential therapeutic targets in several disorders, This review is dedicated to the memory of Prof Geoffrey Burnstock, who passed away on June 2, 2020. He has tirelessly advanced and promoted the research of purinoceptors, which the authors have greatly benefitted from over the years. Thanks, Geoff, for having been such an inspirational mentor. * Daan van der Es [email protected] Xue Yang [email protected] Laura H. Heitman [email protected] Adriaan P. IJzerman [email protected] 1
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands
including Parkinson’s disease, schizophrenia, analgesia, ischemia, and cancer [1]. To date, four subtypes of adenosine receptors have been identified, namely A1, A2A, A2B, and A3. Activation of A1 and A3 receptors leads to inhibition of adenylate cyclase through their interaction with a Gαi protein, whereas A2A and A2B receptors stimulate the enzyme through a GαS-linked pathway. Until now, the 3D structures of the A1 and A2A subtypes have been elucidated [2, 3]; structural studies on the A2B and A3 subtypes have yet to be
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