Benzimidazole-2-carboxylic acid amides and esters: a new structural class of 5-HT3 ligands

A series of novel benzimidazole-2-carboxylic acid amides and esters with a quinuclidine or a tropane moiety were synthesized and evaluated for in vitr o affinity for the 5-HT3, 5-HT4 and D-2 receptors. Compounds 15a, 13j and 1 3h exhibited affinity for the 5-HT3 receptor (K-i = 20.2, 18.4 and 12.7 nM, respectively) and no significant affinity for both 5-HT4 and D-2 receptors . The amide-ester replacement did not induce significant changes in the aff inity profile. The enantioselectivity for the 5-HT3 receptor was reversed w ith regard to the zacopride pattern and the (R)-enantiomer 13c showed highe r affinity (K-i = 56.4 nM) than the (S)-enantiomer 13d (Y = 242.3 nM). An i ncrement of the steric hindrance around the nitrogen atom at the 1-position of the benzimidazole ring led to an improvement in the affinity. The 5-HT3 receptor antagonist activity of compounds with higher affinity was perform ed by evaluating the inhibition of the 5-HT induced von Bezold-Jarisch refl ex. They displayed moderate 5-HT3 antagonist activity (ED50 = 10.6-29.1 mu g/kg i.v.). (C) Elsevier, Paris.