Structure-activity relationships of thiazole and thiadiazole derivatives as potent and selective human adenosine A3 receptor antagonists.

Abstract 4-(4-Methoxyphenyl)-2-aminothiazole and 3-(4-methoxyphenyl)-5-aminothiadiazole derivatives have been synthesized and evaluated as selective antagonists for human adenosine A 3 receptors. A methoxy group in the 4-position of the phenyl ring and N -acetyl or propionyl substitutions of the aminothiazole and aminothiadiazole templates displayed great increases of binding affinity and selectivity for human adenosine A 3 receptors. The most potent A 3 antagonist of the present series, N -[3-(4-methoxy-phenyl)-[1,2,4]thiadiazol-5-yl]-acetamide ( 39 ) exhibiting a K i value of 0.79 nM at human adenosine A 3 receptors, showed antagonistic property in a functional assay of cAMP biosynthesis involved in one of the signal transduction pathways of adenosine A 3 receptors. Molecular modeling study of conformation search and receptor docking experiments to investigate the dramatic differences of binding affinities between two regioisomers of thiadiazole analogues, ( 39 ) and ( 42 ), suggested possible binding mechanisms in the binding pockets of adenosine receptors.