Electrophysiologic characterization of a novel hERG channel activator

Biochem Pharmacol. 2009 Apr 15;77(8):1383-90. doi: 10.1016/j.bcp.2009.01.015. Epub 2009 Feb 3.


Activators of the human ether-a-go-go-related gene (hERG) K(+) channel have been reported recently to enhance hERG current amplitude (five synthetic small molecules and one naturally occurring substance). Here, we characterize the effects of a novel compound A-935142 ({4-[4-(5-trifluoromethyl-1H-pyrazol-3-yl)-phenyl]-cyclohexyl}-acetic acid) on guinea-pig atrial and canine ventricular action potentials (microelectrode techniques) and hERG channels expressed in HEK-293 cells (whole-cell patch clamp techniques). A-935142 shortened cardiac action potentials and enhanced the amplitude of the hERG current in a concentration- and voltage-dependent manner. The fully activated current-voltage relationship revealed that this compound (60 microM) increased both outward and inward K(+) current as well as the slope conductance of the linear portion of the fully activated I-V relation. A-935142 significantly reduced the time constants (tau) of hERG channel activation at two example voltages (-10 mV: tau=100+/-17 ms vs. 164+/-24 ms, n=6, P<0.01; +30 mV: tau=16.7+/-1.8 ms vs. 18.9+/-1.8 ms, n=5, P<0.05) and shifted the voltage-dependence for hERG activation in the hyperpolarizing direction by 9 mV. The time course of hERG channel deactivation was slowed at multiple potentials (-120 to -70 mV). A-935142 also reduced the rate of inactivation and shifted the voltage-dependence of inactivation in the depolarizing direction by 15 mV. Recovery of hERG channel from inactivation was not affected by A-935142. In conclusion, A-935142 enhances hERG current in a complex manner by facilitation of activation, reduction of inactivation, and slowing of deactivation, and abbreviates atrial and ventricular repolarization.

MeSH terms

  • Acetates / chemistry
  • Acetates / pharmacology*
  • Action Potentials / drug effects*
  • Animals
  • Cell Culture Techniques
  • Cell Line
  • Dogs
  • Dose-Response Relationship, Drug
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Guinea Pigs
  • Heart Atria / drug effects
  • Heart Atria / metabolism
  • Humans
  • Ion Channel Gating / drug effects*
  • Molecular Structure
  • Patch-Clamp Techniques
  • Purkinje Fibers / drug effects
  • Purkinje Fibers / metabolism
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Transfection


  • (4-(4-(5-trifluoromethyl-1H-pyrazol-3-yl)phenyl)cyclohexyl)acetic acid
  • Acetates
  • Ether-A-Go-Go Potassium Channels
  • Pyrazoles