文献类型：期刊文献

英文题名：The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer's disease with comorbid depression

作者：Li, Xiaokang[1];Li, Jinwen[1];Huang, Yunyuan[1];Gong, Qi[2];Fu, Yan[2];Xu, Yixiang[1];Huang, Junyang[1];You, Haolan[1];Zhang, Dong[2];Zhang, Dan[2];Mao, Fei[1];Zhu, Jin[1];Wang, Huan[2];Zhang, Haiyan[2];Li, Jian[1,3,4]

机构：[1]East China Univ Sci & Technol, Frontiers Sci Ctr Mat & Dynam Chem, State Key Lab Bioreactor Engn, Sch Pharm,Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Chong Zhi Rd, Shanghai 201203, Peoples R China;[3]Dali Univ, Coll Pharm, Yunnan Key Lab Screening & Res Antipathogen Plant, 5 Xue Ren Rd, Dali 671000, Yunnan, Peoples R China;[4]Tongji Univ, Sch Med, Shanghai Peoples Hosp 10, Clin Med Sci & Tech Innovat Ctr, Shanghai 200092, Peoples R China

年份：2022

卷号：229

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000766121600014)】；

基金：This work was supported by the National Natural Science Foundation of China (81872747, 81903457, 22037002, 81903586, 82173689) , the National Science & Technology Major Projects of China (2018ZX09711002-013-006) , the National Mega-project for Innovative Drugs of China (2019ZX09721001-004-0 03) , the Shanghai Sailing Program (19YF1412600) , and the Shanghai Morning Light Program (18CG33) , the Innovative Research Team of High-level Local Universities in Shanghai, the Chinese Special Fund for State Key Laboratory of Bioreactor Engineering (2060204) , the China Postdoctoral Science Foundation (2018M642121) .

语种：英文

外文关键词：Alzheimer's disease; Depression; Comorbidity; Multi-target-directed ligands

摘要：Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT1A receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT1A receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro, low hERG potassium channel inhibition and accept-able brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression. (c) 2021 Elsevier Masson SAS. All rights reserved.