The structure鈥揳ctivity relationship (SAR) for a novel class of 1,2,4-triazole antagonists of the human A
2A adenosine receptor (hA
2AAR) was explored. Thirty-three analogs of a ligand that was discovered in a structure-based virtual screen against the hA
2AAR were tested in hA
1, A
2A, and A
3 radioligand binding assays and in functional assays for the A
2BAR subtype. As a series of closely related analogs of the initial lead,
1, did not display improved binding affinity or selectivity, molecular docking was used to guide the selection of more distantly related molecules. This resulted in the discovery of
32, a hA
2AAR antagonist (
Ki 200 nM) with high ligand efficiency. In light of the SAR for the 1,2,4-triazole scaffold, we also investigated the binding mode of these compounds based on docking to several A
2AAR crystal structures.
Keywords:
1,2,4-Triazole; A2A adenosine receptor; antagonist; molecular docking; structure鈭抋ctivity relationship