Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels

doi:10.1038/aps.2012.41

	Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels
	Li, Ping 2; Sun, Hai-feng 2; Zhou, Ping-zheng 2; Ma, Chao-ying 1; Hu, Guo-yuan 2; Jiang, Hua-liang2 ; Li, Min 2; Liu, Hong2 ; Gao, Zhao-bing2
刊名	ACTA PHARMACOLOGICA SINICA
	2012-06
卷号	33 期号:6 页码:728-736
关键词	dofetilide DC031050 class III antiarrhythmic agent hERG KCNQ Kv1.2 delayed rectifier potassium current
ISSN号	1671-4083
DOI	10.1038/aps.2012.41
文献子类	Article
英文摘要	Aim: This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels. Methods: Human ether-a-go-go related gene (hERG), KCNQ and Kv1.2 channels were expressed in CHO cells. The delayed rectifier potassium current (I-K) was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-100 Rapid Solution Changer. Results: Both DC031050 and dofetilide potently inhibited hERG currents with IC50 values of 2.3 +/- 1.0 and 17.9 +/- 1.2 nmol/L, respectively. DC031050 inhibited the IK current with an IC50 value of 2.7 +/- 1.5 mu mol/L, which was >1000 times the concentration required to inhibit hERG current. DC031050 at 3 mu mol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of I-K, or the rate of I-K from inactivation. Intracellular application of DC031050 (5 mu mol/L) was insufficient to inhibit I-K. DC031050 up to 10 mu mol/L had no effects on KCNQ2 and Kv1.2 channel currents. Conclusion: DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.
资助项目	National Natural Science Foundation of China[81072579] ; National Natural Science Foundation of China[20872153] ; National Natural Science Foundation of China[81025017]
WOS关键词	METHYLSULFONAMIDO PHENYLETHYLAMINE ANALOGS ; ATRIAL-FIBRILLATION ; K+ CHANNELS ; MYOCARDIAL-INFARCTION ; HIPPOCAMPAL-NEURONS ; BIOLOGICAL ASSAY ; IN-VIVO ; DOFETILIDE ; FLUTTER ; DRUGS
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4552989
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000305034500002
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278050]
专题	药物化学研究室中科院受体结构与功能重点实验室成果转移转化处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	Liu, Hong
作者单位	1.SW Jiaotong Univ, Life Sci & Engn Coll, Chengdu 610031, Peoples R China 2.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Li, Ping,Sun, Hai-feng,Zhou, Ping-zheng,et al. Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels[J]. ACTA PHARMACOLOGICA SINICA,2012,33(6):728-736.
APA	Li, Ping.,Sun, Hai-feng.,Zhou, Ping-zheng.,Ma, Chao-ying.,Hu, Guo-yuan.,...&Gao, Zhao-bing.(2012).Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels.ACTA PHARMACOLOGICA SINICA,33(6),728-736.
MLA	Li, Ping,et al."Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels".ACTA PHARMACOLOGICA SINICA 33.6(2012):728-736.