Pharmacology and Structure of Isolated Conformations of the Adenosine A2A Receptor Define Ligand Efficacy

• DOI: 10.1124/mol.112.084509
• Publication Date: 2013-02-20T05:43:11Z
• Authors: Kirstie A. Bennett; Benjamin Tehan; Guillaume Lebon; Christopher G. Tate; Malcolm Weir; Fiona H. Marshall; Christopher J. La...
• Keywords: Inverse agonist; Xanthine; Docking (animal)

Using isolated receptor conformations crystal structures of the adenosine A_2A have been solved in active and inactive states. Studying change affinity ligands at these allowed qualitative prediction compound efficacy vitro a system-independent manner. Agonist 5′-<i>N</i>-ethylcarboxamidoadenosine displayed clear preference to bind state receptor; inverse agonists (xanthine amine congener, ZM241385, SCH58261, preladenant) bound preferentially state, whereas neutral antagonists (theophylline, caffeine, istradefylline) demonstrated equal for Ligand docking into known rationalized pharmacology observed; agonists, unlike antagonists, cannot be accommodated within agonist-binding site receptor. The availability opens door concept "reverse pharmacology" whereby functional can characterized manner by their pair (or set) G protein–coupled conformations.