Imidazo[1,2-a]quinoxalin-4-amines: A novel class of nonxanthine A1-adenosine receptor antagonists

Abstract The syntheses and A 1 adenosine receptor affinities of a number of imidazo[1,2- a ]quinoxalin-4-amines are reported. Structure—activity relationships within the series and in comparison with other similar tricyclic nonxanthine adenosine antagonists are discussed, leading to a putative common binding mode of these nitrogen-containing heterocycles to A 1 adenosine receptors. Secondary amino compounds displayed the best affinities toward A 1 receptors, while the tertiary amines were almost devoid of activity, thus suggesting a crucial role for the hydrogen bond-forming 4-NH group. Remarkably higher potencies for 1-methyl and N -cyclopentyl derivatives were also found. 4-Cyclopentylamino-1-methylimidazo[1,2- a ]quinoxaline (TRFI 165) is the most potent compound in this series, having K i (A 1 ) = 7.9 nM. It is also provided with a good A 1 selectivity both versus A 2a and A 3 subtypes and was selected for further pharmacological studies.