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

Article abstract of DOI:10.1016/S0223-5234(99)80019-1

The syntheses and A₁ 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 A₁ adenosine receptors. Secondary amino compounds displayed the best affinities toward A₁ 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 (IRFI 165) is the most potent compound in this series, having K(i)(A₁) = 7.9 nM. It is also provided with a good A₁ selectivity both versus A(2a) and A₃ subtypes and was selected for further pharmacological studies.