Discovery of aryl-piperidine derivatives as potential antipsychotic agents using molecular hybridization strategy
| Autor: | Weiqing Peng, Chen Zhu, Wei Fu, Xinwei Li, Wei Li, Bangyi Zhao |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Agonist
Models Molecular medicine.drug_class medicine.medical_treatment Population Pharmacology 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Piperidines Drug Discovery medicine Animals Humans Antipsychotic Receptor education 030304 developmental biology 0303 health sciences Virtual screening education.field_of_study Mice Inbred ICR Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Receptors Dopamine D2 Organic Chemistry General Medicine Receptor antagonist 0104 chemical sciences HEK293 Cells Receptor Serotonin 5-HT1A Serotonin Antagonists Pharmacophore Lead compound Antipsychotic Agents |
| Zdroj: | European journal of medicinal chemistry. 193 |
| ISSN: | 1768-3254 |
| Popis: | 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-HT1A receptor agonist discovered via dynamic pharmacophore-based virtual screening, molecular hybridization strategy was employed to optimize its in vitro activity over D2 and 5-HT2A receptors. The optimized compound 9f was found to show dual potent D2 and 5-HT2A receptors antagonistic activity. In addition, compound 9f showed good in vivo metabolic stability with t1/2 of 2 h in ICR mice and good capability to penetrate the blood-brain barrier with Kp value of 4.03. These results demonstrated that the dual D2 and 5-HT1A receptor antagonist 9f could serve as a promising lead compound to discover potent antipsychotic agents. |
| Databáze: | OpenAIRE |
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