多奈哌齐
药理学
抗抑郁药
乙酰胆碱酯酶
化学
心理学
医学
内科学
神经科学
疾病
痴呆
生物化学
海马体
酶
作者
Xiaokang Li,Yunyuan Huang,Qi Gong,Yan Fu,Yixiang Xu,Junyang Huang,Haolan You,Dong Zhang,Dan Zhang,Fei Mao,Jin Zhu,Huan Wang,Haiyan Zhang,Jian Li
标识
DOI:10.1016/j.ejmech.2021.114045
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 acceptable 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.
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