title: Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents.
abstract: A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (6a-1, 6a-2, 6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound 6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound 6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound 6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound 6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound 6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound 6a-1 exhibited less hepatotoxicity than Agomelatine.
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.|Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ang
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Haiyue
authors.initials: H
authors.lastname: Long
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical and Bioengineering, School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, P. R. China.
authors.forename: Zicheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Liangxue
authors.initials: L
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.|Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, P. R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Biotherapy and Department of Neurosurgery/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Youfu
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015195:Drug Design; D005106:Exploratory Behavior / Q000187:drug effects; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013550:Swimming; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D002118:Calcium; D003345:Corticosterone; D007546:Isoquinolines; D018696:Neuroprotective Agents; C084711:agomelatine; D009281:Naphthalenes; C579455:BDNF protein, human