title: Synthesis and evaluation of amide side-chain modified Agomelatine analogues as potential antidepressant-like agents.
abstract: In this work, nineteen analogues of Agomelatine were readily synthesized through structural modification of the acetamide side-chain starting from the key common intermediate 2-(7-methoxynaphthalen-1-yl) ethanamine (3), which was prepared from commercially available compound 2-(7-methoxynaphthalen-1-yl) acetonitrile (2) in two steps. Corticosterone-induced PC12 pheochromocytoma cells phenotypic in vitro model was utilized to evaluate their potential antidepression activities. Imide compound 4a and acylamino carboxylic acid analogue 5b showed good protective effects on traumatic PC12 cells with protection rates of 34.2% and 23.2%, respectively. Further in vivo assessments in C57 mice FST (forced swim test) model demonstrated that compound 4a significantly reduced the immobility time of the tested subjects, indicating antidepressant-like activity. Preliminary toxicity assays conducted on human normal liver L02 cells and embryonic kidney 293 cells suggested a relatively low safety risk for compound 4a compared with the marketed drugs Agomelatine and Fluoxetine. The promising antidepressant-like efficacy of compound 4a, together with the relatively low toxicity to the normal tested cells and high liability of diffusion through the blood-brain barrier (BBB), presents us insights of exploration of me-better drug candidates of Agomelatine.
authors.affiliation: National Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chang
authors.affiliation: National Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Pi
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Ang
authors.affiliation: National Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Pharmaceutical and Biological Engineering Department, Institute for Chemical Engineering, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Chunlong
authors.initials: C
authors.lastname: Li
authors.affiliation: Pharmaceutical and Biological Engineering Department, Institute for Chemical Engineering, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Jiajia
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Xiong
authors.affiliation: National Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: National Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: luo_youfu@scu.edu.cn.
authors.forename: Youfu
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D000577:Amides / Q000008:administration & dosage / Q000737:chemistry*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D016716:PC12 Cells; D051381:Rats; D013329:Structure-Activity Relationship; D013550:Swimming; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D000577:Amides; D000928:Antidepressive Agents; D003345:Corticosterone; C084711:agomelatine; D009281:Naphthalenes
keywords: Agomelatine; Analogues; Corticosterone; Forced swim test; PC12 cells