Electrophysiologic characterization of a novel hERG channel activator.
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.
Department of Integrative Pharmacology, Abbott Laboratories, R46R-AP9, 100 Abbott Park Road, Abbott Park, IL 60064, USA. zhi.su@abbott.com
Zhi
Z
Su
James
J
Limberis
Andrew
A
Souers
Philip
P
Kym
Ann
A
Mikhail
Kathryn
K
Houseman
Gilbert
G
Diaz
Xiaoqin
X
Liu
Ruth L
RL
Martin
Bryan F
BF
Cox
Gary A
GA
Gintant
D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection
C540927:(4-(4-(5-trifluoromethyl-1H-pyrazol-3-yl)phenyl)cyclohexyl)acetic acid; D000085:Acetates; D051638:Ether-A-Go-Go Potassium Channels; D011720:Pyrazoles