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Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety

文献类型：期刊论文

作者Yang, Wenjiao1,4,5; Gong, Xudong2; Sun, Haiguo3; Wu, Chunhui2; Suo, Jin3; Ji, Jing1,4,5; Jiang, Xiangrui3,4; Shen, Jingshan3,4; He, Yang3,4; Aisa, Haji Akber1,4,5
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-02-05
卷号265页码:20
ISSN号0223-5234
关键词CB2R agonist 5-HT1AR agonist CB1R antagonist Antidepressant Anxiolytic
DOI10.1016/j.ejmech.2023.116048
通讯作者Shen, Jingshan(shenjingshan@simm.ac.cn) ; He, Yang(heyang@simm.ac.cn) ; Aisa, Haji Akber(haji@ms.xjb.ac.cn)
英文摘要Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric dis-orders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3 ' site and the cycloalkyl group at the C-4 ' site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demon-strated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.
WOS关键词FORCED SWIMMING TEST ; ENDOCANNABINOID SYSTEM ; CANNABINOID RECEPTOR ; CANNABIDIOL ; ANTIDEPRESSANT ; INVOLVEMENT ; DERIVATIVES ; ACTIVATION ; MECHANISM ; BEHAVIOR
资助项目Lingang Laboratory[LG- GG-202204-01] ; Lingang Laboratory[LG202103-01-04] ; STI2030-Major Projects[2021ZD0200900]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号WOS:001149710800001
源URL[http://119.78.100.183/handle/2S10ELR8/309079]  
专题中国科学院上海药物研究所
通讯作者Shen, Jingshan; He, Yang; Aisa, Haji Akber
作者单位1.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, State Key Lab Basis Xinjiang Indigenous Med Plant, Urumqi 830011, Peoples R China
2.Vigonvita Shanghai Co Ltd, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Key Lab Plant Resources & Chem Arid Zone, Urumqi 830011, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Wenjiao,Gong, Xudong,Sun, Haiguo,et al. Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,265:20.
APA Yang, Wenjiao.,Gong, Xudong.,Sun, Haiguo.,Wu, Chunhui.,Suo, Jin.,...&Aisa, Haji Akber.(2024).Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,265,20.
MLA Yang, Wenjiao,et al."Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 265(2024):20.

入库方式： OAI收割

来源：上海药物研究所

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