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_1A receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D₂ and 5-HT_2A receptors. The optimized compound 9f was found to show dual potent D₂ and 5-HT_2A receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t_1/2 of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with K_p value of 4.03. These results demonstrated that the dual D₂ and 5-HT_1A receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents.