Derivatives of benzimidazol-2-ylquinoline and benzimidazol-2-ylisoquinoline as selective A1 adenosine receptor antagonists with stimulant activity 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) =1.4 nM) and selectivity against the A(2A) (K(i) >10 μM), A(2B) (K(i)>10 μM), and A(3) ARs (K(i)>1 μM). 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.