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

文献类型：期刊论文

作者Wang, Lei1,2; Qiao, Guan-Hua1,2; Hu, Hai-Ning1; Gao, Zhao-Bing1; Nan, Fa-Jun1
刊名ACS MEDICINAL CHEMISTRY LETTERS
出版日期2019
卷号10期号:1页码:27-33
关键词KCNQ channel retigabine subtype selectivity agonist
ISSN号1948-5875
DOI10.1021/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.
WOS关键词GATED POTASSIUM CHANNELS ; SMOOTH-MUSCLE ; K(V)7 CHANNELS ; KV7 CHANNELS ; SELECTIVE ACTIVATION ; EXPRESSION ; TARGETS ; GENE
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研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000455561600004
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/290773]  
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, 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.

入库方式： OAI收割

来源：上海药物研究所

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