2-Aryl-8-chloro-1,2,4-triazolo[1,5- a]quinoxalin-4-amines as highly potent A 1 and A 3 adenosine receptor antagonists

Abstract

Some 2-aryl-8-chloro-1,2,4-triazolo[1,5- a]quinoxaline derivatives 2– 18, obtained by introducing different substituents on either the 4-amino moiety (acyl or carbamoyl groups) or the 2-phenyl ring (4-OCH 3) of previously reported 8-chloro-2-phenyl-1,2,4-triazolo[1,5- a]quinoxalin-4-amine ( 1), have been synthesized and tested in radioligand binding assays at bovine A 1 and A 2A and at cloned human A 1 and A 3 adenosine receptors. The rationally designed 8-chloro-2-(4-methoxy-phenyl)-1,2,4-triazolo[1,5- a]quinoxalin-4-acetylamine ( 14) can be considered one of the most potent and hA 3 versus hA 1 selective AR antagonists reported till now. The structure–activity relationships of compounds 2– 18 are in agreement with those of previously reported 2-aryl-1,2,4-triazolo[4,3- a]quinoxalines (series A) and 2-arylpyrazolo[3,4- c]quinolines (series B), thus suggesting a similar AR binding mode. In fact, the importance for the A 3 receptor–ligand interaction of both a strong acidic NH proton donor and a C O proton acceptor at position-4, able to engage hydrogen-bonding interactions with specific sites on the A 3 AR, has been confirmed. Using our recently published hA 3 receptor model, to better elucidate our experimental results, we decided to theoretically depict the putative TM binding motif of the herein reported 1,2,4-triazolo[1,5- a]quinoxaline derivatives on human A 3 receptor. Structure–activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.