SPECIFIC BLOCK OF CLONED HERG CHANNELS BY CLOFILIUM AND ITS TERTIARY ANALOG LY97241

The class III antiarrhythmic drug clofilium is known to block diverse delayed rectifier K+ channels at micromolar concentrations. In the pre sent study me investigated the potency of clofilium and its tertiary a nalog LY97241 to inhibit K+ channels, encoded by the human ether-a-go- go related gene (HERG). Clofilium blocked HERG channels in a voltage-d ependent fashion with an IC50 of 250 nM and 150 nM at 0 and (+)40 mV, respectively. LY97241 was almost 10-fold more potent (IC50 of 19 nM at (+)40 mV). Other cloned K+ channels which are also expressed in cardi ac tissue, Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv4.2, Kir2.1, or I-Ks, were no t affected by 100-fold higher concentrations. Block of HERG channels b y LY97241 was voltage dependent and the rate of HERG inactivation was increased by LY97241. A rise of [K+](0) decreased both, rate of HERG i nactivation and LY97241 affinity. The HERG S631A and S620T mutant chan nels which have a strongly reduced degree of inactivation were 7-fold and 33-fold less sensitive to LY97241 blockade, indicating that LY9724 1 binding is affected by HERG channel inactivation. In summary, the an tiarrhythmic action of clofilium and its analog LY97241 appears to be caused by their potent, but distinct ability for blocking HERG channel s. (C) 1997 Federation of European Biochemical Societies.