期刊
ACS CHEMICAL NEUROSCIENCE
卷 8, 期 12, 页码 2708-2721出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.7b00259
关键词
Alzheimer's disease; depression; multitarget-directed ligand; ChE inhibition; 5-HT1A agonist; 5-HT reuptake inhibition
资金
- National Natural Science Foundation of China [21672064, 81522045]
- Shanghai Sailing Program [17YF1403600]
- Fundamental Research Funds for the Central Universities
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据