The human ether-a'-go-go related gene (hERG) K+ channel blockade by the investigative selective-serotonin reuptake inhibitor CONA-437: Limited dependence on s6 aromatic residues

Diverse non-cardiac drugs adversely influence cardiac electrophysiology by inhibiting repolarising k+ currents mediated by channels encoded by the human ether-a-go-go-related gene (herg). in this study,pharmacological blockade of herg k+ channel current (iherg) by a novel investigative serotonin-selective reuptake inhibitor (ssri),cona-437,was investigated. whole-cell patch-clamp measurements of iherg were made from human embryonic kidney (hek 293) cells expressing wildtype (wt) or mutant forms of the herg channel. with a step-ramp voltage-command,peak iherg was inhibited with an ic50 of 1.34 μm at 35 ±1°c; the ic50 with the same protocol was not significantly different at room temperature. voltagecommand waveform selection had only a modest effect on the potency of iherg block: the ic50 with a ventricular action potential command was 0.72 μm. iherg blockade developed rapidly with time following membrane depolarisation and showed a weak dependence on voltage,accompanied by a shift of ~ -5 mv in voltage-dependence of activation. there was no significant effect of cona-437 on voltage-dependence of iherg inactivation,though at some voltages an apparent acceleration of the time-course of inactivation was observed. significantly,mutation of the s6 aromatic amino acid residues y652 and f656 had only a modest effect on iherg blockade by cona-437 (a 3-4 fold shift in affinity). cona-437 at up to 30 μm had no significant effect on either nav1.5 sodium channels or l-type calcium channels. in conclusion,the novel ssri cona-437 is particularly notable as a gating-dependent herg channel inhibitor for which neither s6 aromatic amino-acid constituent of the canonical drug binding site on the herg channel appears obligatory for iherg inhibition to occur.