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

• A series of triazolo-triazines was developed as adenosine receptor (AR) antagonists.
• Compounds show better affinity at the hA2A and hA3 ARs than at the hA1 and hA2B ARs.
• A benzylamino group at the C5 position gives highest affinity values at the hARs.
• Docking simulations were carried out to explain the observed binding data.

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: KihA1 = 94.6 nM; KihA2A = 1.11 nM; IC50hA2B = 2214 nM; KihA3 = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki = 1.44 nM; hA1/hA2A = 216.0; hA3/hA2A = 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 hA2A AR.

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