Abuse of the common anti-diarrheal loperamide is associated with QT interval prolongation as well as development of the potentially fatal arrhythmia torsades de pointes. The mechanism underlying this cardiotoxicity is high affinity inhibition of the human ether-a-go-go-related gene (hERG) cardiac K+ channel. N-Desmethyl loperamide is the major metabolite of loperamide and is a close structural relative of the parent molecule. To date no information is available regarding the affinity of N-desmethyl loperamide for human cardiac ion channels. The effects of N-desmethyl loperamide on various cloned human cardiac ion channels including hERG, KvLQT1/mink and Na_v1.5 were studied and compared to that of the parent. N-Desmethyl loperamide was a much weaker (7.5-fold) inhibitor of hERG compared to loperamide. However, given the higher plasma levels of the metabolite relative to the parent, it is likely that N-desmethyl loperamide can contribute, at least secondarily, to the cardiotoxicity observed with loperamide abuse. We used the recently solved cryo-EM structure of the hERG channel together with previously published inhibitors, to understand the basis of the interactions as well as the difference that a single methyl plays in the hERG channel blocking affinities of these two compounds.

常见的抗腹泻洛哌丁胺的滥用与QT间期的延长以及潜在致命性心律失常性扭转性室速的发展有关。这种心脏毒性的潜在机制是对人类以太相关基因（hERG）心脏K +通道的高度亲和力抑制。N-去甲基洛哌丁胺是洛哌丁胺的主要代谢产物，是母体分子的近亲。迄今为止，尚无关于N-去甲基洛哌丁胺对人心脏离子通道的亲和力的信息。研究了N-去甲基洛哌丁胺对各种克隆的人类心脏离子通道（包括hERG，KvLQT1 / mink和Na _v 1.5）的影响，并与亲本进行了比较。ñ与去甲洛哌丁胺相比，去甲去甲洛哌丁胺是hERG的弱得多（7.5倍）抑制剂。然而，鉴于代谢产物的血浆水平相对于母体更高，N-去甲基洛哌丁胺可能至少在第二方面对滥用洛哌丁胺时观察到的心脏毒性有贡献。我们使用了最近解决的hERG通道的cryo-EM结构以及先前发布的抑制剂，来了解相互作用的基础以及单个甲基在hERG通道中阻断这两种化合物的亲和力的区别。