Adenosine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adenosine Receptors [27]) are activated by the endogenous ligand adenosine (potentially inosine also at A₃ receptors). Crystal and cryo-EM structures for all four adenosine receptors have been solved, occupied by either agonists (sometimes in the presence of an allosteric modulator) or antagonists. Many of these structures were incorporated in a recent review [37]. More recently, structures for the A_2B receptor [12,14] and the A₃ receptor [11,64] were elucidated. The A_2A receptor is used as a workhorse in GPCR structure elucidation: almost 100 structures are available in the Protein Data Bank (www.rcsb.org). Istradefylline, a selective A_2A receptor antagonist, is on the market for the treatment of Parkinson's disease, while caffeine's mechanism of action is largely due to its antagonism of at least three of the four adenosine receptor subtypes. Allosteric modulators, particular PAMs of A₁ and A₃ receptors, have been explored chemically and structurally [20,66].

Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A_2B adenosine receptor (ADORA2BP1) with 79% identity to the A_2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor [42]. DPCPX also exhibits antagonism at A_2B receptors (pK_i ca. 7,[2,54]). Antagonists at A₃ receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A₃ receptor. In the absence of other adenosine receptors, [³H]DPCPX and [³H]ZM 241385 can also be used to label A_2B receptors (K_D ca. 30 and 60 nM respectively). [¹²⁵I]AB-MECA also binds to A₁ receptors [54]. [³H]CGS 21680 is relatively selective for A_2A receptors, but may also bind to other sites in cerebral cortex [16,48]. [³H]NECA binds to other non-receptor elements, which also recognise adenosine [59].

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Subcommittee members: Adriaan P. IJzerman (Chairperson) Professor of Medicinal Chemistry Leiden-Amsterdam Centre for Drug Research Gorlaeus Laboratories, Leiden University PO Box 9502 Leiden, 2300 RA, The Netherlands Bertil B. Fredholm (Past chairperson) Department of Physiology and Pharmacology Section of Molecular Neuropharmacology Karolinska Institutet Stockholm, 171 77, Sweden Kenneth A. Jacobson Molecular Recognition Section National Institutes of Health Building 8A, Room BIA-17 Bethesda, MD, 20892, USA Joel Linden La Jolla Institute for Allergy & Immunology 9420 Athena Circle La Jolla, CA 92037 USA Christa E. Müller University of Bonn Pharmaceutical Institute Department of Pharmaceutical & Medicinal Chemistry D-53121 Bonn (Endenich) Germany Lauren May Cardiac GPCR Biology Lab Drug Discovery Biology Theme Monash Institute of Pharmaceutical Sciences Monash University Parkville VIC 3052 Australia

Other contributors: Bruno G. Frenguelli (Past chairperson) Department of Biological Sciences University of Warwick Coventry CV4 7AL UK Rebecca Hills (Past curator) (Past curator) Karl-Norbert Klotz Institut für Pharmakologie und Toxikologie Universität Würzburg D-97078 Würzburg Germany