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

doi:10.1038/s41401-019-0267-z

	Discovery of aryl sulfonamide-selective Nav1.7 inhibitors with a highly hydrophobic ethanoanthracene core
	Wang, Jin-tao 1,2; Zheng, Yue-ming 1; Chen, Yue-ting 1; Gu, Min 1; Gao, Zhao-bing 1; Nan, Fa-jun 1
刊名	ACTA PHARMACOLOGICA SINICA
	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
DOI	10.1038/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.
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关键词	GATED SODIUM-CHANNELS ; OF-FUNCTION MUTATIONS ; NA(V)1.7 INHIBITORS ; ANALGESIC EFFICACY ; ANIMAL-MODELS ; ACETIC-ACID ; PAIN ; ACTIVATION ; TARGET ; GENE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000514159600001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281275]
专题	中国科学院上海药物研究所
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.