Quinolinedione nucleus as a novel scaffold for A1 and A2A adenosine receptor antagonists

In the last few years, much effort has been directed towards the synthesis of selective adenosine receptor (AR) antagonists since they are attractive tools for pharmacological intervention in many pathophysiological conditions. During our studies aimed at obtaining new nonclassical adenosine antagonists devoid of phosphodiesterase (PDE) inhibition, a series of 2-pyridones and 2,5-quinolinediones (3a-f, 5a-f, 6a,c-f) has been synthesized as potential AR ligands. Binding affinities of the new compounds were determined for bovine and human adenosine A(1), A(2A), and A(3) receptors. Compound 5f showed good affinity (K (i) = 7.8 mu M) towards human A(1)AR but no selectivity (K (i) = 7.0 mu M) towards human A(2A)AR, whereas compound 6f showed more affinity towards human A(2A) (K (i) = 16 mu M) than A(1) receptor (percentage inhibition at 10 mu M concentration = 11). In the 1-100 mu M range, the new compounds did not inhibit cardiac PDE3 activity at all. Molecular modeling studies carried out on 5f and 6f support the pharmacological results and suggest 6f as a potential lead compound selective towards A(2A)AR.