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Study on structure-activity relationship (SAR) of simplified mirogabalin derivatives as voltage-gated calcium channel alpha 2 delta ligands for the treatment of chronic neuropathic pain

文献类型：期刊论文

作者Zhang, Yuanwen2,3; Zheng, Yueming1; Wu, Qingqing3; Tian, Fuyun1,3; Ma, Chuanjun4,5; Xu, Haiyan1; Zhan, Li1; Gao, Zhaobing1,3; Zhao, Guilong1,3; Ti, Huihui2
刊名MEDICINAL CHEMISTRY RESEARCH
出版日期2022-12-26
页码26
关键词Voltage-gated calcium channel alpha 2 delta subunit gamma-aminobutyric acid Mirogabalin Neuropathic pain Structure-activity relationship
ISSN号1054-2523
DOI10.1007/s00044-022-03006-6
通讯作者Gao, Zhaobing(zbgao@simm.ac.cn) ; Zhao, Guilong(guilong@126.com) ; Ti, Huihui(tihuihui@126.com)
英文摘要A clinical therapy for chronic neuropathic pain is urgently needed, and the voltage-gated calcium channel (VGCC) alpha 2 delta subunit is among the most promising therapeutic targets. To intensively explore the structure-activity relationship (SAR) of the lipophilic moiety in VGCC alpha 2 delta subunit ligands (gabapentinoids), we designed and synthesized 11 bicyclic and monocyclic derivatives based on mirogabalin, a third-generation VGCC alpha 2 delta subunit ligand. The competitive binding of the synthesized compounds to the human VGCC alpha 2 delta-1 subunit was measured in vitro, and the results demonstrated that the lipophilic moiety size was strictly limited in gabapentinoids, in which conformationally rigid bicylo[3.2.0]heptane/heptene with a cis-fusion was the most preferred structure. In contrast, monocyclic cyclobutane was associated with a markedly decreased binding affinity except in 4 (IC50=15.2nM), in which the substituents could mimic the rigid conformation of bicylo[3.2.0]heptane/heptene; heteroatoms in the lipophilic moiety were detrimental to the binding affinity (2, IC50>729nM). The SAR findings obtained in the present study will be valuable for designing novel gabapentinoid drugs to treat chronic neuropathic pain in the future. [Graphical ]
WOS关键词GABAPENTIN ; REARRANGEMENT ; PHARMACOLOGY ; OXETANE ; SUBUNIT
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000904006200003
出版者SPRINGER BIRKHAUSER
源URL[http://119.78.100.183/handle/2S10ELR8/303802]  
专题中国科学院上海药物研究所
通讯作者Gao, Zhaobing; Zhao, Guilong; Ti, Huihui
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Guangdong Pharmaceut Univ, Sch Chinese Med Resource, Guangzhou 510006, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China
4.Shandong First Med Univ, Sch Chem & Pharmaceut Engn, Tai An 271016, Shandong, Peoples R China
5.Shandong Acad Med Sci, Tai An 271016, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Yuanwen,Zheng, Yueming,Wu, Qingqing,et al. Study on structure-activity relationship (SAR) of simplified mirogabalin derivatives as voltage-gated calcium channel alpha 2 delta ligands for the treatment of chronic neuropathic pain[J]. MEDICINAL CHEMISTRY RESEARCH,2022:26.
APA Zhang, Yuanwen.,Zheng, Yueming.,Wu, Qingqing.,Tian, Fuyun.,Ma, Chuanjun.,...&Ti, Huihui.(2022).Study on structure-activity relationship (SAR) of simplified mirogabalin derivatives as voltage-gated calcium channel alpha 2 delta ligands for the treatment of chronic neuropathic pain.MEDICINAL CHEMISTRY RESEARCH,26.
MLA Zhang, Yuanwen,et al."Study on structure-activity relationship (SAR) of simplified mirogabalin derivatives as voltage-gated calcium channel alpha 2 delta ligands for the treatment of chronic neuropathic pain".MEDICINAL CHEMISTRY RESEARCH (2022):26.

入库方式： OAI收割

来源：上海药物研究所

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