Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

Zhou, Peng; Babcock, Joseph J.; Liu, Lianqing; Li, Min; Gao, Zhao

doi:10.1038/aps.2011.70

Cited by 57 publications

(46 citation statements)

References 37 publications

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“…However, the seizure phenotype is obviously more common in LQT2 (36/77, 47%) than average and all other subtypes of LQT syndrome. Inhibition of the hERG channel by drugs causes acquired LQT2 (Roden, 2004;Perrin et al, 2008;Berger et al, 2010;Zhou et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

Chen

Zhang

et al. 2014

J Pharmacol Exp Ther

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Human ether-a-go-go-related gene (hERG) and KCNQ channels are two classes of voltage-gated potassium channels. Specific mutations have been identified that are causal for type II long QT (LQT2) syndrome, neonatal epilepsy, and benign familial neonatal convulsions. Increasing evidence from clinical studies suggests that LQT2 and epilepsy coexist in some patients. Therefore, an integral approach to investigating and treating the two diseases is likely more effective. In the current study, we found that NS1643 [1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea], a previously reported hERG activator, is also an activator of KCNQ channels. It potentiates the neuronal KCNQ2, KCNQ4, and KCNQ2/Q3 channels, but not the cardiac KCNQ1. The effects of NS1643 on the KCNQ2 channel include left shifting of voltage for reaching 50% of the maximum conductance and slowing of deactivation. Analysis of the dose-response curve of NS1643 revealed an EC 50 value of 2.44 6 0.25 mM. A hydrophobic phenylalanine (F137) located at the middle region of the voltage-sensing domain was identified as critical for NS1643 activity on KCNQ2. When testing NS1643 effects in rescuing LQT2 hERG mutants and the KCNQ2 BFNC mutants, we found it is particularly efficacious in some cases. Considering the substantial relationship between LQT2 and epilepsy, these findings reveal that NS1643 is a useful compound to elucidate the causal connection of LQT2 and epilepsy. More generally, this may provide a strategy in the development of therapeutics for LQT2 and epilepsy.

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Section: Discussionmentioning

confidence: 99%

The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

Chen

Zhang

et al. 2014

J Pharmacol Exp Ther

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“…So far, there are approximately 13 reported hERG activators: RPR260243, PD118057, PD307243, NS1643, NS3623, ICA-105574, KB130015, A-935142, mallotoxin, matrine, oxymatrine, carbachol, and [18,[83][84][85][86][87] . Activators prefer to regulate the hERG channel by altering channel kinetics [18] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

“…Activators are divided into seven types based on their mechanism of activation: (1) RPR260243 mainly affects the hERG channel by altering deactivation [18,88] . (2) PD118057, PD307243, NS1643, NS3623, and ICA-105574 all influence the hERG channel by regulating inactiva tion [18,19,84,[88][89][90] . (3) KB130015 regulates the hERG channel by increasing activation [18] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

“…For example, RPR260243 is able to reverse dofentilide-induced APD prolongation by slowing down hERG deactivation to increase I [kr] [ [18][19][20] . In addition, PD118057 can reduce hERG inactivation, shift up inactivation potential and prevent dofetilide-caused QT interval prolongation [18,84] . However, PD118057 fails to correct the dominant-negative effect of the E637K-hERG [91] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

“…However, PD118057 fails to correct the dominant-negative effect of the E637K-hERG [91] . ICA-105574 can also disable hERG inactivation and shorten the QT interval in cardiomyocytes [18,84] . Moreover, matrine and oxymatrine can also rescue arsenic trioxide-induced hERG deficiency and APD prolongation [22] .…”

Section: Existing and Potential Rescue Strategiesmentioning

confidence: 99%

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Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

Zhang

Yang

2014

Acta Pharmacol Sin

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The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia. Diverse drugs have been removed from the market owing to their inhibitory activity on the hERG channel and their contribution to acquired long QT syndrome (LQTS). Moreover, mutations that cause hERG channel dysfunction may induce congenital LQTS. Recently, an increasing number of biochemical and molecular mechanisms underlying hERG-associated LQTS have been reported. In fact, numerous potential biochemical and molecular rescue strategies are hidden within the biogenesis and regulating network. So far, rescue strategies of hERG channel dysfunction and LQTS mainly include activators, blockers, and molecules that interfere with specific links and other mechanisms. The aim of this review is to discuss the rescue strategies based on hERG channel toxicology from the biochemical and molecular perspectives.

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hERG stereoselective modulation by mexiletine‐derived ureas: Molecular docking study, synthesis, and biological evaluation

Milani

Budriesi

Tavazzani

et al. 2023

Archiv der Pharmazie

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Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life‐threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether‐à‐go‐go‐related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine‐derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)‐8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug‐induced forms of LQTS.

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Activation of human ether-a-go-go related gene (hERG) potassium channels by small molecules

Cited by 57 publications

References 37 publications

The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

The Human Ether-A-Go-Go–Related Gene Activator NS1643 Enhances Epilepsy-Associated KCNQ Channels

Translational toxicology and rescue strategies of the hERG channel dysfunction: biochemical and molecular mechanistic aspects

hERG stereoselective modulation by mexiletine‐derived ureas: Molecular docking study, synthesis, and biological evaluation

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