School of Pharmacy & Minhang Hospital, Fudan University, Shanghai, 201301, PR China.
School of Pharmacy & Minhang Hospital, Fudan University, Shanghai, 201301, PR China.
Eur J Med Chem. 2020 May 1;193:112214. doi: 10.1016/j.ejmech.2020.112214. Epub 2020 Mar 10.
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.
精神分裂症是一种慢性、致残性精神障碍，影响着全球约 1%的人口。研究表明，作用于多个靶点的药物比作用于单一靶点的药物在治疗精神分裂症方面具有更优异的疗效。在这项研究中，基于通过动态药效基团虚拟筛选发现的选择性强效 5-HT 受体激动剂 FW01，采用分子杂交策略对其在 D 和 5-HT 受体上的体外活性进行优化。优化后的化合物 9f 被发现具有双重强效 D 和 5-HT 受体拮抗活性。此外，化合物 9f 在 ICR 小鼠中具有良好的体内代谢稳定性，t1/2 为 2 小时，K 值为 4.03，表明其具有良好的穿透血脑屏障的能力。这些结果表明，双重 D 和 5-HT 受体拮抗剂 9f 可以作为一种有前途的先导化合物，用于发现有效的抗精神病药物。
