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The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG.
J Pharmacol Exp Ther. 1998 Aug; 286(2):788-93.JP

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 microM. 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.

Authors+Show Affiliations

Hoechst Marion Roussel, Inc., Cincinnati, Ohio.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9694935

Citation

Rampe, D, et al. "The Antipsychotic Agent Sertindole Is a High Affinity Antagonist of the Human Cardiac Potassium Channel HERG." The Journal of Pharmacology and Experimental Therapeutics, vol. 286, no. 2, 1998, pp. 788-93.
Rampe D, Murawsky MK, Grau J, et al. The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. J Pharmacol Exp Ther. 1998;286(2):788-93.
Rampe, D., Murawsky, M. K., Grau, J., & Lewis, E. W. (1998). The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. The Journal of Pharmacology and Experimental Therapeutics, 286(2), 788-93.
Rampe D, et al. The Antipsychotic Agent Sertindole Is a High Affinity Antagonist of the Human Cardiac Potassium Channel HERG. J Pharmacol Exp Ther. 1998;286(2):788-93. PubMed PMID: 9694935.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. AU - Rampe,D, AU - Murawsky,M K, AU - Grau,J, AU - Lewis,E W, PY - 1998/8/8/pubmed PY - 1998/8/8/medline PY - 1998/8/8/entrez SP - 788 EP - 93 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 286 IS - 2 N2 - 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 microM. 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9694935/The_antipsychotic_agent_sertindole_is_a_high_affinity_antagonist_of_the_human_cardiac_potassium_channel_HERG_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9694935 DB - PRIME DP - Unbound Medicine ER -