Synthesis and SAR studies of trisubstituted purinones as potent and selective adenosine A2A receptor antagonists

A series of trisubstituted purinones was synthesized and evaluated as A_2A receptor antagonists. The A_2A structure–activity relationships at the three substituted positions were studied and selectivity against the A₁ receptor was investigated. One antagonist 12o exhibits a K_i of 9 nM in an A_2A binding assay, a K_b of 18 nM in an A_2A cAMP functional assay, and is 220-fold selective over the A₁ receptor.