Design,synthesis and evaluation of vilazodone-tacrine hybrids as multitarget-directed ligands against depression with cognitive impairment |
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Authors: | Wenwen Liu Huan Wang Xiaokang Li Yixiang Xu Jian Zhang Wei Wang Qi Gong Xiaoxia Qiu Jin Zhu Fei Mao Haiyan Zhang Jian Li |
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Affiliation: | 1. 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. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 201203, China;4. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China |
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Abstract: | 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 vilazodone-tacrine 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?μM, BuChE IC50?=?0.34?±?0.03?μM; 2a, AChE IC50?=?2.36?±?0.34?μM, BuChE IC50?=?0.10?±?0.01?μM). 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. |
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Keywords: | Depression Cognitive impairment Multitarget-directed ligand 5-HT reuptake inhibition ChE inhibition |
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