5-Amino-2-phenyl[1,2,3]triazolo[1,2-alpha][1,2,4]benzotriazin-1-one:A Versatile Scaffold To Obtain Potent and Selective A3 Adenosine Receptor Antagonists

摘要

Binding assays on human A1,A_(2A),and A3 adenosine receptors(ARs)and functional studies on A_(2B)ARs revealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII,previously reported as ligands at the central benzodiazepine receptor(BzR),possess nanomolar affinity at the A3 AR.Replacement of the amide of VIII with an amidine moiety gave the 5-amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-ones IX,which maintain a nanomolar potency at the A3 AR with selectivity over the BzR.Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivity over the A1,A_(2A),and A_(2B)ARS.The best result of our lead optimization efforts is 9-chloro-5-(4-methoxybenzoyl)amino-2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1-one(23),which displayed a K_i of 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR.Docking simulations on selected ligands into a model of the A3 AR allowed us to rationalize the structure-activity relationships of phenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level.