THE ANTIPSYCHOTIC AGENT SERTINDOLE IS A HIGH-AFFINITY ANTAGONIST OF THE HUMAN CARDIAC POTASSIUM CHANNEL HERG

Acquired long QT syndrome is a side effect seen with some pharmacologi cal 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 prol ongation 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 transfec ted 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 depolarizatio n to +20 mV. When currents were measured at the end of prolonged (20 s ec) depolarizing pulses, the IC50 of sertindole measured 2.99 nM. Sert indole enhanced the rate of current decay during these prolonged volta ge steps and displayed a positive voltage dependence. Sertindole was a pproximately 1000-foId less active at blocking Kv1.5 displaying an IC5 0 value of 2.12 mu M. By comparison, the potent class III antiarrhythm ic agent dofetilde blocked HERO 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 c ardiac potassium channel HERG and that this blockade underlies the pro longation of QT interval observed with this drug. Furthermore, the ser tindole molecule may provide a useful starting point far the developme nt of very high affinity ligands for HERG.