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

The syntheses and A(1) adenosine receptor affinities of a number of imidazo [1,2-alpha]quinoxalin-4-amines are reported. Structure activity relationshi ps within the series and in comparison with other similar tricyclic nonxant hine adenosine antagonists are discussed, leading to a putative common bind ing mode of these nitrogen-containing heterocycles to A(1) adenosine recept ors. Secondary amino compounds displayed the best affinities toward A(1) re ceptors, while the tertiary amines were almost devoid of activity, thus sug gesting a crucial role for the hydrogen bond-forming 4-NH group. Remarkably higher potencies for l-methyl and N-cyclopentyl derivatives were also foun d. 4-Cyclopentylamino-1-methylimidazo[1,2-alpha]quinoxaline (IRFI 165) is t he most potent compound in this series, having K-i(A(1)) = 7.9 nM. It is al so provided with a good A(1) selectivity both versus A(2a) and A(3) subtype s and was selected for further pharmacological studies. (C) Elsevier, Paris .