Discovery of aryl-piperidine derivatives as potential antipsychotic agents using molecular hybridization strategy.

Schizophrenia is a chronic, disabling mental disorder that affects about one percent of world's population. Drugs acting on multiple targets have been demonstrated to provide superior efficacy in schizophrenia than agents acting on single target. In this study, based on FW01, a selective potent 5-HT receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D and 5-HT receptors. The optimized compound 9f was found to show dual potent D and 5-HT receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with K value of 4.03. These results demonstrated that the dual D and 5-HT receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents.