Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel

Human ether-a-go-go-related gene (HERG) encodes the alpha-subunit of channels carrying the cardiac rapid delayed K+ current (I-Kr), 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 (I-HERG) of clemastine, a conventional antihistamine that has been associated with delayed ventricular repolarization in vitro, but for which no adverse effects oil the human QT interval have been reported. Whole-cell patch-clamp measurements of I-HERG were made at 37 degrees C front human embryonic kidney (HEK 293) cells stably expressing HERG channels. I-HERG tails at -40 mV following depolarizing pulses to + 20 mV were inhibited by clemastine with ail IC50 Value of 12 nM: this drug concentration also produced it marked inhibition of peak I-HERG elicited during an AP voltage-clamp command. Clemastine produced a reversible similar to-5 mV shift in the I-HERG steady-state voltage-dependent activation curve, but voltage-dependence of inactivation was unaffected. Development Of I-HERG 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 I-HERG 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 I-HERG 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. (c) 2005 Elsevier Ltd. All rights reserved.