5,7-Disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as pharmacological tools to explore the antagonist selectivity profiles toward adenosine receptors

Abstract The structure–activity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5- a ][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes ( 10 : K i hA 1  = 94.6 nM; K i hA 2A  = 1.11 nM; IC 50 hA 2B  = 2214 nM; K i hA 3  = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA 2A AR antagonist ( 14 : hA 2A AR K i  = 1.44 nM; hA 1 /hA 2A  = 216.0; hA 3 /hA 2A  = 20.6). This trend diverges from the analysis on the pyrazolo[4,3- e ][1,2,4]triazolo[1,5- c ]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA 2A AR.