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Acta Pharmacol Sin. 2012 Jun;33(6):728-36. doi: 10.1038/aps.2012.41. Epub 2012 May 21.

Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels.

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1
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.

Abstract

AIM:

This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels.

METHODS:

Human ether-à-go-go related gene (hERG), KCNQ and Kv1.2 channels were expressed in CHO cells. The delayed rectifier potassium current (I(K)) was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-100 Rapid Solution Changer.

RESULTS:

Both DC031050 and dofetilide potently inhibited hERG currents with IC(50) values of 2.3 ± 1.0 and 17.9 ± 1.2 nmol/L, respectively. DC031050 inhibited the I(K) current with an IC(50) value of 2.7 ± 1.5 μmol/L, which was >1000 times the concentration required to inhibit hERG current. DC031050 at 3 μmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of I(K), or the rate of I(K) from inactivation. Intracellular application of DC031050 (5 μmol/L) was insufficient to inhibit I(K). DC031050 up to 10 μmol/L had no effects on KCNQ2 and Kv1.2 channel currents.

CONCLUSION:

DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.

PMID:
22609836
PMCID:
PMC4085657
DOI:
10.1038/aps.2012.41
[Indexed for MEDLINE]
Free PMC Article
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