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 +/- 0.1 microM and a Hill slope (n(H)) of 3.3 +/- 0.2. The effect on hERG channels was confirmed because the known hERG channel blockers, N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide, 2HCl (E-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 microM) shifts the midpoint of the voltage-dependence of inactivation by >180 mV from -86 to +96 mV. In addition to the effects on inactivation, greater concentrations of ICA-105574 (3 microM) produced comparatively small hyperpolarizing shifts (up to 11 mV) in the voltage-dependence of channel activation and a 2-fold slowing of channel deactivation. In isolated guinea pig ventricular cardiac myocytes, ICA-105574 induced a concentration-dependent shortening of action potential duration (>70%, 3 microM) 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.

中文翻译：

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通过3-硝基-N-（4-苯氧基苯基）苯甲酰胺（ICA-105574）去除与人类醚相关的基因钾通道失活的药理作用。

人源于去往相关基因（hERG）的钾通道活性有助于塑造心脏动作电位并影响其持续时间。在这项研究中，我们报告了3-硝基-N-（4-苯氧基苯基）苯甲酰胺（ICA-105574）的发现，这是一种有效而有效的hERG通道激活剂，具有独特的作用机理。在重组hERG通道的全细胞膜片钳研究中，ICA-105574的陡峭增强电流幅度超过10倍，EC（50）值为0.5 +/- 0.1 microM，希尔斜率（n（H））为3.3 +/- 0.2。由于已知的hERG通道阻滞剂N- [4-[[1- [2-（6-甲基-2-吡啶基）乙基] -4-哌啶基]羰基]苯基]甲磺酰胺2HCl（ E-4031）和BeKm-1，有效地阻止了ICA-105574的刺激作用。ICA-105574增强hERG通道活性的主要机制是消除hERG通道失活，因为ICA-105574（2 microM）将失活的电压依赖性中点从-86改变了> 180 mV至+96 mV。除了对失活的影响外，更高浓度的ICA-105574（3 microM）在通道激活的电压依赖性和通道失活的2倍减慢方面产生了相对较小的超极化位移（最高11 mV）。在分离的豚鼠心室心肌细胞中，ICA-105574诱导了动作电位持续时间的浓度依赖性缩短（> 70％，3 microM），这可以通过与E-4031预孵育来防止。总之，我们确定了一种可以防止hERG钾通道失活的新型药物。