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Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core

文献类型：期刊论文

作者Wang, Jin-tao1,2; Zheng, Yue-ming1; Chen, Yue-ting1; Gu, Min1; Gao, Zhao-bing1; Nan, Fa-jun1
刊名ACTA PHARMACOLOGICA SINICA
出版日期2020-03-01
卷号41期号:3页码:293-302
关键词Nav1 7 sodium channel aryl sulfonamide maprotiline compound 10o electrophysiology acetic acid-induced visceral pain analgesic activity
ISSN号1671-4083
DOI10.1038/s41401-019-0267-z
通讯作者Gao, Zhao-bing(zbgao@simm.ac.cn) ; Nan, Fa-jun(fjnan@simm.ac.cn)
英文摘要Nav1.7 channels are mainly distributed in the peripheral nervous system. Blockade of Nav1.7 channels with small-molecule inhibitors in humans might provide pain relief without affecting the central nervous system. Based on the facts that many reported Nav1.7-selective inhibitors contain aryl sulfonamide fragments, as well as a tricyclic antidepressant, maprotiline, has been found to inhibit Nav1.7 channels, we designed and synthesized a series of compounds with ethanoanthracene and aryl sulfonamide moieties. Their inhibitory activity on sodium channels were detected with electrophysiological techniques. We found that compound 10o potently inhibited Nav1.7 channels stably expressed in HEK293 cells (IC50 = 0.64 +/- 0.30 nmol/L) and displayed a high Nav1.7/Nav1.5 selectivity. In mouse small-sized dorsal root ganglion neurons, compound 10o (10, 100 nmol/L) dose-dependently decreased the sodium currents and dramatically suppressed depolarizing current-elicited neuronal discharge. Preliminary in vivo experiments showed that compound 10o possessed good analgesic activity: in a mouse visceral pain model, administration of compound 10o (30-100 mg/kg, i.p.) effectively and dose-dependently suppressed acetic acid-induced writhing.
WOS关键词GATED SODIUM-CHANNELS ; OF-FUNCTION MUTATIONS ; NA(V)1.7 INHIBITORS ; ANALGESIC EFFICACY ; ANIMAL-MODELS ; ACETIC-ACID ; PAIN ; ACTIVATION ; TARGET ; GENE
资助项目National Science Fund for Distinguished Young Scholars[81825021] ; National Natural Science Foundation of China[81603096] ; National Natural Science Foundation of China[81773707]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000514159600001
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/281275]  
专题新药研究国家重点实验室
通讯作者Gao, Zhao-bing; Nan, Fa-jun
作者单位1.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, CAS Key Lab Receptor Res,State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Jin-tao,Zheng, Yue-ming,Chen, Yue-ting,et al. Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core[J]. ACTA PHARMACOLOGICA SINICA,2020,41(3):293-302.
APA Wang, Jin-tao,Zheng, Yue-ming,Chen, Yue-ting,Gu, Min,Gao, Zhao-bing,&Nan, Fa-jun.(2020).Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core.ACTA PHARMACOLOGICA SINICA,41(3),293-302.
MLA Wang, Jin-tao,et al."Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core".ACTA PHARMACOLOGICA SINICA 41.3(2020):293-302.

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来源：上海药物研究所

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