Electrophysiologic characterization of a novel hERG channel activator

Su, Zhi; Limberis, James T.; Souers, Andrew J.; Kym, Philip R.; Mikhail, Ann; Houseman, Kathryn; Diaz, Gilbert; Liu, Xiaoqin; Martin, Ruth L.; Cox, Bryan F.; Gintant, Gary A.

doi:10.1016/j.bcp.2009.01.015

Cited by 41 publications

(57 citation statements)

References 33 publications

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“…Importantly, an increased ability to withstand triggering activity in the form of mimicked EADs was also demonstrated (100, 168,169). Similar results have been obtained with A-935142 in guinea pigs and dogs (411). PD-118057 has also been tested ex vivo in iso- A: K V 11.1 gating kinetics.…”

Section: B Strategies For Treatment Of Vfmentioning

confidence: 55%

“…A reduction in relative inactivation, being equal to a rightward shifted inactivation curve, will increase the overall K V 11.1 current. Compounds with such properties include NS1643 and NS3623 (both NeuroSearch), PD-307243 (Pfizer), and A-935142 (Abbott) (151,168,169,411,498). RPR260243 (Sanofi-Aventis) utilizes a different mechanism of action, as it slows K V 11.1 channel closure (deactivation) corresponding to an increase in macroscopic I Kr (203).…”

Section: B Strategies For Treatment Of Vfmentioning

confidence: 99%

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Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

202

197

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About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K+ channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K+ channels drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K+ channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure. The underlying posttranscriptional and posttranslational remodeling of the individual K+ channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry arrhythmia.

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Section: B Strategies For Treatment Of Vfmentioning

confidence: 55%

Section: B Strategies For Treatment Of Vfmentioning

confidence: 99%

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Schmitt

Grunnet

Olesen

2014

Physiological Reviews

202

197

View full text Add to dashboard Cite

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“…Although much of the focus has been on compounds that inhibit hERG, because of their potential for proarrhythmic activity, several recent studies have identified and characterized pharmacological agents that enhance hERG activity rather than inhibit these channels. Examples of such agents include RPR260243, (Kang et al, 2005), PD-307243 (Gordon et al, 2008), PD-118057 (Zhou et al, 2005), NS1643 (Casis et al, 2006), NS3623 (Hansen et al, 2006b), mallotoxin (Zeng et al, 2006), and A-935142 (Su et al, 2009). These chemical agents increase current flow through hERG channels via a variety of mechanisms that include depolarizing shifts in the voltage-dependence of inactivation, hyperpolarizing shifts in the voltagedependence of activation, slowing of channel deactivation, or a combination of the above.…”

mentioning

confidence: 99%

Pharmacological Removal of Human Ether-à-go-go-Related Gene Potassium Channel Inactivation by 3-Nitro-N-(4-phenoxyphenyl) Benzamide (ICA-105574)

Gerlach¹,

Stoehr²,

Castle³

2010

Molecular Pharmacology

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Human ether-à -go-go-related gene (hERG) potassium channel activity helps shape the cardiac action potential and influences its duration. In this study, we report the discovery of 3-nitro-N-(4-phenoxyphenyl) benzamide (ICA-105574), a potent and efficacious hERG channel activator with a unique mechanism of action. In whole-cell patch-clamp studies of recombinant hERG channels, ICA-105574 steeply potentiated current amplitudes more than 10-fold with an EC 50 value of 0.5 Ϯ 0.1 M and a Hill slope (n H ) of 3.3 Ϯ 0.2. The effect on hERG channels was confirmed because the known hERG channel blockers, -4031) and BeKm-1, potently blocked the stimulatory effects of ICA-105574. The primary mechanism by which ICA-105574 potentiates hERG channel activity is by removing hERG channel inactivation, because ICA-105574 (2 M) shifts the midpoint of the voltagedependence of inactivation by Ͼ180 mV from Ϫ86 to ϩ96 mV. In addition to the effects on inactivation, greater concentrations of ICA-105574 (3 M) produced comparatively small hyperpolarizing shifts (up to 11 mV) in the voltagedependence of channel activation and a 2-fold slowing of channel deactivation. In isolated guinea pig ventricular cardiac myocytes, ICA-105574 induced a concentrationdependent shortening of action potential duration (Ͼ70%, 3 M) that could be prevented by preincubation with E-4031. In conclusion, we identified a novel agent that can prevent the inactivation of hERG potassium channels. This compound may provide a useful tool to further understand the mechanism by which hERG channels inactivate and affect cardiac function in addition to the role of hERG channels in other cell systems.

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“…Specifically, 60 µmol/L of A-935142 significantly accelerates the activation time constant of hERG channels from 164±24 ms to 100±17 ms and left-shifts the voltage-dependence of activation. A-935142 also reduces the rate of inactivation, right-shifts the voltage-dependence of inactivation, and slows hERG channel deactivation at voltage potentials from -120 to -70 mV [29] .…”

Section: A-935142 A-935142 [{4-[4-(5-trifluoromethyl-1h-pyrazol-3-yl)mentioning

confidence: 99%

“…However, due to the limitations of existing high throughput screening methods and difficulties in assaying the channel on a large scale, few activators have been reported. Most of the existing activators originated from combinatorial chemistry libraries, including RPR260243 [22][23][24] , PD-118057 [25] , PD-307243 [26] , NS1643 [27] , NS3623 [28] , A-935142 [29] , ICA-105574 [30] , and KB130015 [31] . Addi-www.nature.com/aps Zhou PZ et al Acta Pharmacologica Sinica npg tionally, a natural product, mallotoxin, has also been shown to activate hERG [32] .…”

Section: Herg Activatorsmentioning

confidence: 99%

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

et al. 2011

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Human ether-a-go-go related gene (hERG) potassium (K + ) channels play a critical role in cardiac action potential repolarization. Mutations that reduce hERG conductance or surface expression may cause congenital long QT syndrome (LQTS). Moreover, the channels can be inhibited by structurally diverse small molecules, resulting in an acquired form of LQTS. Consequently, small molecules that increase the hERG current may be of value for treatment of LQTS. So far, nine hERG activators have been reported. The aim of this review is to discuss recent advances concerning the identification and action mechanism of hERG activators.

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Electrophysiologic characterization of a novel hERG channel activator

Cited by 41 publications

References 33 publications

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Cardiac Potassium Channel Subtypes: New Roles in Repolarization and Arrhythmia

Pharmacological Removal of Human Ether-à-go-go-Related Gene Potassium Channel Inactivation by 3-Nitro-N-(4-phenoxyphenyl) Benzamide (ICA-105574)

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

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