Discovery of a retigabine derivative that inhibits KCNQ2 potassium channels

doi:10.1038/aps.2013.79

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	Discovery of a retigabine derivative that inhibits KCNQ2 potassium channels
	Hu, Hai-ning 1,2; Zhou, Ping-zheng 3; Chen, Fei 1,2; Li, Min 3; Nan, Fa-jun1,2 ; Gao, Zhao-bing3
刊名	ACTA PHARMACOLOGICA SINICA
	2013-10
卷号	34 期号:10 页码:1359-1366
关键词	KCNQ2 channel retigabine HN38 XE991 structure modification CHO cell whole-cell recording
ISSN号	1671-4083
DOI	10.1038/aps.2013.79
文献子类	Article
英文摘要	Aim: Retigabine, an activator of KCNQ2-5 channels, is currently used to treat partial-onset seizures. The aim of this study was to explore the possibility that structure modification of retigabine could lead to novel inhibitors of KCNQ2 channels, which were valuable tools for KCNQ channel studies. Methods: A series of retigabine derivatives was designed and synthesized. KCNQ2 channels were expressed in CHO cells. KCNQ2 currents were recorded using whole-cell voltage clamp technique. Test compound in extracellular solution was delivered to the recorded cell using an ALA 8 Channel Solution Exchange System. Results: A total of 23 retigabine derivatives (HN31-HN410) were synthesized and tested electrophysiologically. Among the compounds, HN38 was the most potent inhibitor of KCNQ2 channels (its IC50 value=0.10 +/- 0.05 mu mol/L), and was 7-fold more potent than the classical KCNQ inhibitor XE991. Further analysis revealed that HN38 (3 mu mol/L) had no detectable effect on channel activation, but accelerated deactivation at hyperpolarizing voltages. In contrast, XE991 (3 mu mol/L) did not affect the kinetics of channel activation and deactivation. Conclusion: The retigabine derivative HN38 is a potent KCNQ2 inhibitor, which differs from XE991 in its influence on the channel kinetics. Our study provides a new strategy for the design and development of potent KCNQ2 channel inhibitors.
资助项目	National Science and Technology Major Project on "Key New Drug Creation and Manufacturing Program"[2013ZX09103001-016] ; National Key Basic Research Program of China[2013CB910604] ; National Natural Science Foundation of China for Excellent Key Laboratory[81123004]
WOS关键词	LINOPIRDINE
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000325276400012
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277444]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室神经药理学研究国际科学家工作站
通讯作者	Nan, Fa-jun
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Hu, Hai-ning,Zhou, Ping-zheng,Chen, Fei,et al. Discovery of a retigabine derivative that inhibits KCNQ2 potassium channels[J]. ACTA PHARMACOLOGICA SINICA,2013,34(10):1359-1366.
APA	Hu, Hai-ning,Zhou, Ping-zheng,Chen, Fei,Li, Min,Nan, Fa-jun,&Gao, Zhao-bing.(2013).Discovery of a retigabine derivative that inhibits KCNQ2 potassium channels.ACTA PHARMACOLOGICA SINICA,34(10),1359-1366.
MLA	Hu, Hai-ning,et al."Discovery of a retigabine derivative that inhibits KCNQ2 potassium channels".ACTA PHARMACOLOGICA SINICA 34.10(2013):1359-1366.