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

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

  • Eur J Med Chem. 2022 Feb 5;229:114045. doi: 10.1016/j.ejmech.2021.114045.
Xiaokang Li 1,  Jinwen Li 1,  Yunyuan Huang 1,  Qi Gong 2,  Yan Fu 2,  Yixiang Xu 1,  Junyang Huang 1,  Haolan You 1,  Dong Zhang 2,  Dan Zhang 2,  Fei Mao 1,  Jin Zhu 1,  Huan Wang 3,  Haiyan Zhang 4,  Jian Li 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China.
  • 2 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 3 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. Electronic address: hwang1990@simm.ac.cn.
  • 4 CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. Electronic address: hzhang@simm.ac.cn.
  • 5 State Key Laboratory of Bioreactor Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai, 200237, China; Yunnan Key Laboratory of Screening and Research on Anti-pathogenic Plant Resources from West Yunnan, College of Pharmacy, Dali University, 5 Xue Ren Road, Dali, Yunnan, 671000, China; Clinical Medicine Scientific and Technical Innovation Center, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200092, China. Electronic address: jianli@ecust.edu.cn.
PMID: 34922191 DOI: 10.1016/j.ejmech.2021.114045
Abstract

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.

Keywords

Alzheimer's disease; Comorbidity; Depression; Multi-target-directed ligands.

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