Design and synthesis of new benzimidazole-arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands

A series of new benzimidazole-arylpiperazine derivatives III were designed, synthesized and evaluated for binding affinity at serotoninergic 5-HT1A and 5-HT3 receptors. Compound IIIc was identified as a novel mixed 5-HT1A/5-HT3 ligand with high affinity for both serotonin receptors and excellent selectivity over α1-adrenergic and dopamine D2 receptors. This compound was characterized as a partial agonist at 5-HT1ARs and a 5-HT3R antagonist, and was effective in preventing the cognitive deficits induced by muscarinic receptor blockade in a passive avoidance learning test.