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Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel.
J Mol Cell Cardiol. 2006 Jan; 40(1):107-18.JM

Abstract

Human ether-à-go-go-related gene (HERG) encodes the alpha-subunit of channels carrying the cardiac rapid delayed K+ current (Ikr), which is a major determinant of the duration of ventricular action potentials (APs) and of the QT interval. This study investigated the effects on HERG channel current (IHERG) of clemastine, a "conventional" antihistamine that has been associated with delayed ventricular repolarization in vitro, but for which no adverse effects on the human QT interval have been reported. Whole-cell patch-clamp measurements of IHERG were made at 37 degrees C from human embryonic kidney (HEK 293) cells stably expressing HERG channels. IHERG tails at -40 mV following depolarizing pulses to +20 mV were inhibited by clemastine with an IC50 value of 12 nM; this drug concentration also produced a marked inhibition of peak IHERG elicited during an AP voltage-clamp command. Clemastine produced a reversible approximately -5 mV shift in the IHERG steady-state voltage-dependent activation curve, but voltage-dependence of inactivation was unaffected. Development of IHERG inhibition by clemastine showed strong time-dependence. The S6 point mutations Y652A and F656A greatly attenuated the inhibitory effect of clemastine. We conclude that clemastine is a high potency inhibitor of IHERG, that this action is contingent upon channel gating and that clemastine interacts with a high affinity drug-binding site in the HERG channel pore cavity. The disparity between clemastine's potent IHERG inhibition and a lack of QT-prolongation in normal clinical use underscores the need to interpret HERG IC50 data for novel compounds in the context of information from other safety assays.

Authors+Show Affiliations

Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University Walk, Bristol BS8 1TD, UK.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16288909

Citation

Ridley, John M., et al. "Clemastine, a Conventional Antihistamine, Is a High Potency Inhibitor of the HERG K+ Channel." Journal of Molecular and Cellular Cardiology, vol. 40, no. 1, 2006, pp. 107-18.
Ridley JM, Milnes JT, Hancox JC, et al. Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel. J Mol Cell Cardiol. 2006;40(1):107-18.
Ridley, J. M., Milnes, J. T., Hancox, J. C., & Witchel, H. J. (2006). Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel. Journal of Molecular and Cellular Cardiology, 40(1), 107-18.
Ridley JM, et al. Clemastine, a Conventional Antihistamine, Is a High Potency Inhibitor of the HERG K+ Channel. J Mol Cell Cardiol. 2006;40(1):107-18. PubMed PMID: 16288909.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel. AU - Ridley,John M, AU - Milnes,James T, AU - Hancox,Jules C, AU - Witchel,Harry J, Y1 - 2005/11/09/ PY - 2005/06/20/received PY - 2005/09/21/revised PY - 2005/09/26/accepted PY - 2005/11/18/pubmed PY - 2006/3/11/medline PY - 2005/11/18/entrez SP - 107 EP - 18 JF - Journal of molecular and cellular cardiology JO - J Mol Cell Cardiol VL - 40 IS - 1 N2 - Human ether-à-go-go-related gene (HERG) encodes the alpha-subunit of channels carrying the cardiac rapid delayed K+ current (Ikr), which is a major determinant of the duration of ventricular action potentials (APs) and of the QT interval. This study investigated the effects on HERG channel current (IHERG) of clemastine, a "conventional" antihistamine that has been associated with delayed ventricular repolarization in vitro, but for which no adverse effects on the human QT interval have been reported. Whole-cell patch-clamp measurements of IHERG were made at 37 degrees C from human embryonic kidney (HEK 293) cells stably expressing HERG channels. IHERG tails at -40 mV following depolarizing pulses to +20 mV were inhibited by clemastine with an IC50 value of 12 nM; this drug concentration also produced a marked inhibition of peak IHERG elicited during an AP voltage-clamp command. Clemastine produced a reversible approximately -5 mV shift in the IHERG steady-state voltage-dependent activation curve, but voltage-dependence of inactivation was unaffected. Development of IHERG inhibition by clemastine showed strong time-dependence. The S6 point mutations Y652A and F656A greatly attenuated the inhibitory effect of clemastine. We conclude that clemastine is a high potency inhibitor of IHERG, that this action is contingent upon channel gating and that clemastine interacts with a high affinity drug-binding site in the HERG channel pore cavity. The disparity between clemastine's potent IHERG inhibition and a lack of QT-prolongation in normal clinical use underscores the need to interpret HERG IC50 data for novel compounds in the context of information from other safety assays. SN - 0022-2828 UR - https://www.unboundmedicine.com/medline/citation/16288909/Clemastine_a_conventional_antihistamine_is_a_high_potency_inhibitor_of_the_HERG_K+_channel_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(05)00311-1 DB - PRIME DP - Unbound Medicine ER -