Derivatives of benzimidazol-2-yl-quinoline and benzimidazol-2-yl-isoquinoline as selective antagonists at A1 adenosine receptors with stimulant actions on human colon motility

A number of quinolines and isoquinolines connected in various ways to a substituted benzimidazol-2-yl system were synthesized and evaluated as novel antagonists of adenosine receptors (ARs) by competition experiments using human A 1, A 2A, and A 3 ARs. The new compounds were designed based on derivatives of 2-(benzimidazol-2-yl)quinoxaline, previously reported as potent and selective antagonists of A 1 and A 3 ARs. Among these, 3-[4-(ethylthio)-1H-benzimidazol-2-yl]isoquinoline 4b exhibited the best combination of potency toward the A 1 AR (K i=1.4nM) and selectivity against the A 2A (K i>10μm), A 2B (K i>10μm), and A 3 ARs (K i>1μM). Functional experiments in circular smooth muscle preparations of isolated human colon showed that 4b behaves as a potent and selective antagonist of the A 1 AR in the neuromuscular compartment of this intestinal region. Biological and pharmacological data suggest that 4b is a suitable starting point for the development of novel agents endowed with stimulant properties on colonic activity.