Uncarialins J-M from Uncaria rhynchophylla and Their Anti-depression Mechanism in Unpredictable Chronic Mild Stress-Induced Mice via Activating 5-HT_(1A) Receptor  

作　　者：Zhen-Long Yu Rong Bai Jun-Jun Zhou Hui-Lian Huang Wen-Yu Zhao Xiao-Kui Huo Ya-Hui Yang Zhi-Lin Luan Bao-Jing Zhang Cheng-Peng Sun Xiao-Chi Ma 

机构地区：[1]Dalian Key Laboratory of Metabolic Target Characterization and Traditional Chinese Medicine Intervention,National&Local Joint Engineering Research Center for Drug Development of Neurodegenerative Disease,College of Pharmacy,College(Institute)of Integrative Medicine,Dalian Medical University,Dalian,Liaoning 116044,China [2]Department of Pharmacy,Shanghai East Hospital,Tongji University,Shanghai 200120,China [3]Laboratory of Modern Preparation of Traditional Chinese Medicine,Ministry of Education,Jiangxi University of Traditional Chinese Medicine,Nanchang,Jiangxi 330103,China

出　　处：《Chinese Journal of Chemistry》2021年第5期1331-1343,共13页中国化学（英文版）

基　　金：the Dalian Science and Technology Leading Talents Project(No.2019RD15);the Distinguished Professor of Liaoning Province,the Open Research Fund of the State Key Laboratory of Cognitive Neuroscience and Learning(No.CNLZD1801);the Natural Science Foundation of Liaoning Province(No.2020-MS-256);the Dalian Young Star of Science and Technology(No.2019RQ123);the Shanghai"Rising Stars of Medical Talent" Youth Development Program-Youth Medical Talents-Clinical Pharmacist Program(No.SHWJRS(2019)_072).

摘　　要：Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history.After investigation of U.rhynchophylla,eleven monoterpene indole alkaloids,including four new compounds uncarialins J-M(1-4)and seven known analogues(5-11),were isolated and identified.Their structural characterization was conducted using HRESIMS,1D and 2D NMR,electronic circular dichroism(ECD)spectra,and quantum chemical computations.Compounds 1,2,7,and 9-11 displayed significant ag-onistic effects towards 5-HT_(1A) receptor,and their EC_(50) values were 7.86,732,2.24,1.18,1.52,and 3.75μmol/L,respectively.Furthermore,in vivo experimental results fully revealed that hirsuteine(7)displayed a significant antidepression effect in unpredictable chronic mild stress(UCMS)-induced depression mice mainly via regulating 5-HT_(1A) signaling pathway.Molecular docking and site-directed amino acid mutation verified that amino acid residues Aspll6 and Asn386 were the binding sites of hirsuteine(7)with 5-HT_(1A) receptor.In addition,pre-treatment of mice with WAY 100635 also blocked the anti-depression effect of hirsuteine(7),which further demonstrated that 5-HT_(1A) receptor was a potential target of hirsuteine(7)to effectively treat depression.These findings indicated the therapeutic material basis of U.rhynchophylla and the anti-depression underlying mechanism of hirsuteine(7),and further provided the useful guidance for the development of hirsuteine(7)as a potential antidepressant candidate.

关 键 词：Monoterpene indole alkaloids Hirsuteine DEPRESSION 5-HT_(1A)receptor Site-directed amino acid mutation 

分 类 号：O62[理学—有机化学]