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Research ArticleArticle

The Antipsychotic Agent Sertindole is a High Affinity Antagonist of the Human Cardiac Potassium Channel HERG

David Rampe, Michael K. Murawsky, Jessica Grau and Eric W. Lewis
Journal of Pharmacology and Experimental Therapeutics August 1998, 286 (2) 788-793;
David Rampe
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Michael K. Murawsky
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Jessica Grau
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Eric W. Lewis
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Abstract

Acquired long QT syndrome is a side effect seen with some pharmacological agents, including antipsychotic drugs, and is associated with the development of ventricular arrhythmias. This syndrome is often caused by the blockade of repolarizing potassium channels the human heart. A new antipsychotic agent, sertindole, has been shown to produce QT prolongation after therapeutic doses in humans. We therefore examined the effects of sertindole on two cloned human cardiac potassium channels, the human ether-a-go-go-related gene (HERG) and Kv1.5, stably transfected into mammalian cell lines. Using patch clamp electrophysiology, we found sertindole blocked HERG currents with an IC50 value of 14.0 nM when tail currents at −40 mV were measured after a 2-sec depolarization to +20 mV. When currents were measured at the end of prolonged (20 sec) depolarizing pulses, the IC50 of sertindole measured 2.99 nM. Sertindole enhanced the rate of current decay during these prolonged voltage steps and displayed a positive voltage dependence. Sertindole was approximately 1000-fold less active at blocking Kv1.5 displaying an IC50 value of 2.12 μM. By comparison, the potent class III antiarrhythmic agent dofetilde blocked HERG with an IC50 value of 9.50 nM but did not enhance HERG current decay or block Kv1.5 channel currents. It is concluded that sertindole is a high affinity antagonist of the human cardiac potassium channel HERG and that this blockade underlies the prolongation of QT interval observed with this drug. Furthermore, the sertindole molecule may provide a useful starting point for the development of very high affinity ligands for HERG.

Footnotes

  • Send reprint requests to: Dr. David Rampe, Hoechst Marion Roussel, Inc., Route 202–206, P.O. Box 6800, Bridgewater, NJ 08807-0800.

  • Abbreviations:
    HERG
    humanether-a-go-go-related gene
    Kv1.5
    ultra-rapidly activating delayed rectifier K+ channel
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    • Received January 12, 1998.
    • Accepted April 7, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 286, Issue 2
1 Aug 1998
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Research ArticleArticle

The Antipsychotic Agent Sertindole is a High Affinity Antagonist of the Human Cardiac Potassium Channel HERG

David Rampe, Michael K. Murawsky, Jessica Grau and Eric W. Lewis
Journal of Pharmacology and Experimental Therapeutics August 1, 1998, 286 (2) 788-793;

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Research ArticleArticle

The Antipsychotic Agent Sertindole is a High Affinity Antagonist of the Human Cardiac Potassium Channel HERG

David Rampe, Michael K. Murawsky, Jessica Grau and Eric W. Lewis
Journal of Pharmacology and Experimental Therapeutics August 1, 1998, 286 (2) 788-793;
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