Benzimidazole derivatives. 2. Synthesis and structure-activity relationships of new azabicyclic benzimidazole-4-carboxylic acid derivatives with affinity for serotoninergic 5-HT3 receptors

Abstract

A new series of azabicyclic benzimidazole-4-carboxamides 2-21 and - carboxylates 22-30 were synthesized and evaluated for binding affinity at serotoninergic 5-HT3 and 5-HT4 receptors in the CNS. Most of the synthesized compounds exhibited high or very high affinity for the 5-HT3 binding site and low to no significant affinity for the 5-HT4 receptor. SAR observations indicated that a halogen atom at the 6-position and a nitro group at the 7-position of the benzimidazole ring is the best substitution pattern for 5-HT3 affinity and 5-HT3/5-HT4 selectivity, as well as no substitution in this ring. (S)-(-)-N-(Quinuclidin-3-yl)benzimidazole-4- carboxamides 2, 8, and 14 bound at central 5-HT3 sites with high affinity (K(i) = 2.6, 0.13, and 1.7 nM, respectively) and excellent selectivity over serotonin 5-HT4 and 5-HT(1A) receptors (K(i) > 1000-10000 nM). Furthermore, these new 5-HT3 receptor ligands were pharmacologically characterized as potent and selective 5-HT3 antagonists in the isolated guinea pig ileum (pA2 = 9.6, 9.9, and 9.1, respectively).