Abstract
Using isolated receptor conformations crystal structures of the adenosine A2A receptor have been solved in active and inactive states. Studying the change in affinity of ligands at these conformations allowed qualitative prediction of compound efficacy in vitro in a system-independent manner. Agonist (NECA) displayed clear preference to bind to active state receptor; inverse agonists (XAC, ZM241385, SCH58261 and preladenant) bound preferentially to the inactive state whilst neutral antagonists (theophylline, caffeine and istradefylline) demonstrated equal affinity for active and inactive states. Ligand docking into the known crystal structures of the A2A receptor rationalised the pharmacology observed; inverse agonists, unlike neutral antagonists, cannot be accommodated within the agonist-binding site of the receptor. The availability of isolated receptor conformations opens the door to the concept of 'reverse pharmacology', whereby the functional pharmacology of ligands can be characterised in a system-independent manner by their affinity for a pair (or set) of GPCR conformations.
- Received December 18, 2012.
- Revision received February 15, 2013.
- Accepted February 19, 2013.
- The American Society for Pharmacology and Experimental Therapeutics