Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent

doi:10.1038/aps.2012.119

	Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent
	Bai, Dong-lu2 ; Chen, Wei-zhou 1; Bo, Yun-xin 2; Dong, Yue-li 1; Kang, Ai-li 2; Sun, Wei-kang 1; Wang, Wei 1; Hu, Zhong-liang 2; Wang, Yi-ping1
刊名	ACTA PHARMACOLOGICA SINICA
	2012-09
卷号	33 期号:9 页码:1176-1186
关键词	sulcardine sulcardine sulfate changrolin heart arrhythmias aconitine ouabain sodium current L-type calcium current
ISSN号	1671-4083
DOI	10.1038/aps.2012.119
文献子类	Article
英文摘要	Aim: To investigate the anti-arrhythmic effects of sulfamide analogues of changrolin and to characterize the sulfate of compound 6f (sulcardine sulfate, Sul) as a novel anti-arrhythmic agent. Methods: The anti-arrhythmic effects of compounds were studied against aconitine-induced arrhythmias in rats and ouabain-induced arrhythmias in guinea pigs. The effects of Sul on transmembrane action potentials were investigated in isolated rabbit sinoatrial nodes and guinea-pig papillary muscles using intracellular recording. With a whole-cell recording technique, the effects of Sul on sodium current, calcium current, and potassium currents were examined in isolated single guinea-pig ventricular myocytes. Results: In aconitine-induced arrhythmias of rats, sulfamide analogues of changrolin (4, 5, and 6a-6p) exhibited various anti-arrhythmic activities. The sulfate of compound 6f (Sul) increased the amount of aconitine required to induce arrhythmias in each treated animal. The ED50 value of Sul in rats was 196 mg/kg. In ouabain-induced arrhythmias of guinea pigs, 25, 50, and 100 mg/kg doses of Sul increased the dose of ouabain required to induce VP, VT, and VF in a dose-dependent manner. In papillary preparations, Sul produced a concentration-dependent decrease in APA and V-max, prolonged APD(90) and ERP, whereas RP was unaffected. In the spontaneously beating sinus nodes, Sul reduced APA and V-max in a concentration-dependent manner. The whole-cell recording studies revealed that Sul produced a reversible reduction in I-Na (IC50=26.9 mu mol/L) and I-Ca,I-L (IC50= 69.2 mu mol/L), whereas the inward rectifier (I-K1) and the delayed rectifier potassium currents (I-K) were unaffected. Conclusion: As a multi-ion channel blocker, Sul may have potent efficacy in anti-atrial and ventricular arrhythmias.
资助项目	Shanghai Committee of Science and Technology, China[975419000-4] ; Ministry of Science and Technology of China[2002AA2Z3123] ; Ministry of Science and Technology of China[2005AA2Z3D60] ; Ministry of Science and Technology of China[2008ZX09101-004]
WOS关键词	PARASYMPATHOLYTIC PROPERTIES ; SUBSTITUTED PHENOLS ; DERIVATIVES ; CHANGROLIN ; MYOCYTES
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4635869
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000308391000010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277966]
专题	院士及顾问专家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药理学第一研究室
通讯作者	Bai, Dong-lu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Dept Pharmacol, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Bai, Dong-lu,Chen, Wei-zhou,Bo, Yun-xin,et al. Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent[J]. ACTA PHARMACOLOGICA SINICA,2012,33(9):1176-1186.
APA	Bai, Dong-lu.,Chen, Wei-zhou.,Bo, Yun-xin.,Dong, Yue-li.,Kang, Ai-li.,...&Wang, Yi-ping.(2012).Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent.ACTA PHARMACOLOGICA SINICA,33(9),1176-1186.
MLA	Bai, Dong-lu,et al."Discovery of N-(3,5-bis(1-pyrrolidylmethyl)-4-hydroxybenzyl)-4-methoxybenzenesulfamide (sulcardine) as a novel anti-arrhythmic agent".ACTA PHARMACOLOGICA SINICA 33.9(2012):1176-1186.