文献类型：期刊文献

英文题名：Novel Vilazodone Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation

作者：Li, Xiaokang[1];Wang, Huan[2,3];Xu, Yixiang[1];Liu, Wenwen[1];Gong, Qi[2];Wang, Wei[2];Qiu, Xiaoxia[1];Zhu, Jin[1];Mao, Fei[1];Zhang, Haiyan[2];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;[3]Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

年份：2017

卷号：8

期号：12

起止页码：2708

外文期刊名：ACS CHEMICAL NEUROSCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000418786100019)】；

基金：Financial support for this research was provided by the National Natural Science Foundation of China (Grants 21672064, 81522045), Shanghai Sailing Program (Grants 17YF1403600), and the Fundamental Research Funds for the Central Universities.

语种：英文

外文关键词：Alzheimer's disease; depression; multitarget-directed ligand; ChE inhibition; 5-HT1A agonist; 5-HT reuptake inhibition

摘要：Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC50 = 3.319 +/- 0.708 mu M), 5-HT1A agonist (EC50 = 107 +/- 37 nM), and 5-HT reuptake inhibition (IC50 = 76.3 +/- 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e center dot HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.