Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity

doi:10.1021/acsmedchemlett.8b00315

	Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity
	Wang, Lei 1,2; Qiao, Guan-Hua 1,2; Hu, Hai-Ning 1; Gao, Zhao-Bing 1; Nan, Fa-Jun 1
刊名	ACS MEDICINAL CHEMISTRY LETTERS
	2019
卷号	10 期号:1 页码:27-33
关键词	KCNQ channel retigabine subtype selectivity agonist
ISSN号	1948-5875
DOI	10.1021/acsmedchemlett.8b00315
通讯作者	Gao, Zhao-Bing(zbgao@simm.ac.cn) ; Nan, Fa-Jun(fjnan@simm.ac.cn)
英文摘要	Recent research suggests that KCNQ isoforms, particularly the KCNQ4 and KCNQS subtypes expressed in smooth muscle cells, are involved in both establishing and maintaining resting membrane potentials and regulating smooth muscle contractility. Retigabine (RTG) is a first-in-class antiepileptic drug that potentiates neuronal KCNQpotassium channels, but poor subtype selectivity limits its further application as a pharmacological tool. In this study, we improved the subtype specificity of retigabine by altering the N-1/3 substituents and discovered several compounds that show better selectivity for KCNQ4 and KCNQS channels. Among these compounds, 10g is highly selective for KCNQ4 and KCNQS channels without potentiating KCNQ1 and KCNQ2 channels. These results are an advance in the exploration of small molecule modifiers that selectively activate different KCNQ isoforms. The developed compounds could also serve as new pharmacological tools for elucidating the function of KCNQ channels natively expressed in various tissues.
资助项目	National Natural Science Foundation of China[81773707] ; Science and Technology Commission of Shanghai Municipality[16431901700] ; Science and Technology Commission of Shanghai Municipality[15431901500]
WOS关键词	GATED POTASSIUM CHANNELS ; SMOOTH-MUSCLE ; K(V)7 CHANNELS ; KV7 CHANNELS ; SELECTIVE ACTIVATION ; EXPRESSION ; TARGETS ; GENE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000455561600004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/290773]
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, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Wang, Lei,Qiao, Guan-Hua,Hu, Hai-Ning,et al. Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity[J]. ACS MEDICINAL CHEMISTRY LETTERS,2019,10(1):27-33.
APA	Wang, Lei,Qiao, Guan-Hua,Hu, Hai-Ning,Gao, Zhao-Bing,&Nan, Fa-Jun.(2019).Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity.ACS MEDICINAL CHEMISTRY LETTERS,10(1),27-33.
MLA	Wang, Lei,et al."Discovery of Novel Retigabine Derivatives as Potent KCNQ4 and KCNQ5 Channel Agonists with Improved Specificity".ACS MEDICINAL CHEMISTRY LETTERS 10.1(2019):27-33.