Benzimidazole derivatives. Part 5: Design and synthesis of new benzimidazole–arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands Original Research Article

A series of new mixed benzimidazole–arylpiperazine derivatives were designed by incorporating in general structure III the pharmacophoric elements of 5-HT1A and 5-HT3 receptors. Compounds 1–11 were synthesized and evaluated for binding affinity at both serotoninergic receptors, all of them exhibiting high 5-HT3R affinity (Ki = 10–62 nM), and derivatives with an o-alkoxy group in the arylpiperazine ring showing nanomolar affinity for the 5-HT1AR (Ki = 18–150 nM). Additionally, all the synthesized compounds were selective over α1-adrenergic and dopamine D2 receptors (Ki>1000–10,000 nM). Compound 3 was selected for further pharmacological characterization due to its interesting binding profile as mixed 5-HT1A/5-HT3 ligand with high affinity for both receptors (5-HT1A: Ki = 18.0 nM, 5-HT3: Ki = 27.2 nM). In vitro and in vivo findings suggest that this compound acts as a partial agonist at 5-HT1ARs and as a 5-HT3R antagonist. This novel mixed 5-HT1A/5-HT3 ligand was also effective in preventing the cognitive deficits induced by muscarinic receptor blockade in a passive avoidance learning test, suggesting a potential interest in the treatment of cognitive dysfunction.