| Abstract
| - Binding assays on human A1, A2A, and A3 adenosine receptors (ARs) and functional studies on A2B ARsrevealed that various 2-phenyl[1,2,3]triazolo[1,2-a][1,2,4]benzotriazin-1,5(6H)-diones VIII, previouslyreported 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 overthe BzR. Insertion of a p-methoxybenzoyl at the 5-amino moiety enhanced A3 AR affinity and selectivityover the A1, A2A, and A2B 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 Kiof 1.6 nM at the A3 AR and no significant affinity at the other ARs or the BzR. Docking simulations onselected ligands into a model of the A3 AR allowed us to rationalize the structure−activity relationships ofphenyltriazolobenzotriazindiones VIII and aminophenyltriazolobenzotriazinones IX at the molecular level.
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