文献类型：期刊文献

英文题名：Design, synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment

作者：Liu, Wenwen[1];Wang, Huan[2,4];Li, Xiaokang[1];Xu, Yixiang[1];Zhang, Jian[2];Wang, Wei[2];Gong, Qi[2];Qiu, Xiaoxia[1];Zhu, Jin[1];Mao, Fei[1];Zhang, Haiyan[2,3];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, 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 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China;[3]Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;[4]Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China

年份：2018

卷号：26

期号：12

起止页码：3117

外文期刊名：BIOORGANIC & MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000436779400005)】；

基金：Financial support for this research was provided by the National Natural Science Foundation of China (Grants 21702061, 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：Depression; Cognitive impairment; Multitarget-directed ligand; 5-HT1A agonist; 5-HT reuptake inhibition; ChE inhibition

摘要：Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodonetacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT1A agonist activities (1d, EC50 = 0.36 +/- 0.08 nM; 2a, EC50 = 0.58 +/- 0.14 nM) and 5-HT reuptake inhibitory activities (1d, IC50 = 20.42 +/- 6.60 nM; 2a, IC50 = 22.10 +/- 5.80 nM). In addition, they showed moderate ChE inhibitory activities (1d, AChE IC50 = 1.72 +/- 0.217 mu M, BuChE IC50 = 0.34 +/- 0.03 mu M; 2a, AChE IC50 = 2.36 +/- 0.34 mu M, BuChE IC50 = 0.10 +/- 0.01 mu M). Good multitarget activities with goodt blood-brain barrier permeability of 1d and 2a make them good lead compounds for the further study of depression with cognitive impairment. (C) 2018 Elsevier Ltd. All rights reserved.