A molecular simplification approach of previously reported 2-arylpyrazolo[3,4-c]quinolin-4-ones was applied to design 2-arylpyrazolo[4,3-d]pyrimidin-7-one derivatives as new human A3 adenosine receptor antagonists. Substituents with different lipophilicity and steric hindrance were introduced at the 5-position of the bicyclic scaffold (R5 = H, Me, Et, Ph, CH2Ph) and on the 2-phenyl ring (OMe, Me). Most of the synthesized derivatives were highly potent hA3 adenosine receptor antagonists, the best being the 2-(4-methoxyphenyl)pyrazolo[4,3-d]pyrimidin-7-one (Ki = 1.2 nM). The new compounds were also highly selective, being completely devoid of affinity toward hA1, hA2A, and hA2B adenosine receptors. On the basis of the recently published human A2A receptor crystallographic information, we propose a novel receptor-driven hypothesis to explain both A3 AR affinity and A3 versus A2A selectivity profiles of these new antagonists
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