title: 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.
abstract: 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 (I(hERG)) by a novel investigative serotonin-selective reuptake inhibitor (SSRI), CONA-437, was investigated. Whole-cell patch-clamp measurements of I(hERG) were made from human embryonic kidney (HEK 293) cells expressing wild-type (WT) or mutant forms of the hERG channel. With a step-ramp voltage-command, peak I(hERG) was inhibited with an IC(50) of 1.34 μM at 35 ±1°C; the IC(50) with the same protocol was not significantly different at room temperature. Voltage-command waveform selection had only a modest effect on the potency of I(hERG) block: the IC50 with a ventricular action potential command was 0.72 μM. I(hERG) 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 I(hERG) 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 I(hERG) 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 I(hERG) inhibition to occur.
authors.affiliation: Pfizer Neusentis, The Portway Building, Granta Park, Cambridge, CB21 6GS, United Kingdom. jules.hancox@bristol.ac.uk.
authors.forename: A J
authors.initials: AJ
authors.lastname: Alexandrou
authors.forename: J T
authors.initials: JT
authors.lastname: Milnes
authors.forename: S Z
authors.initials: SZ
authors.lastname: Sun
authors.forename: B
authors.initials: B
authors.lastname: Fermini
authors.forename: S C
authors.initials: SC
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Jenkinson
authors.forename: D J
authors.initials: DJ
authors.lastname: Leishman
authors.forename: H J
authors.initials: HJ
authors.lastname: Witchel
authors.forename: J C
authors.initials: JC
authors.lastname: Hancox
authors.forename: J L
authors.initials: JL
authors.lastname: Leaney
mesh_terms: D000818:Animals; D016466:CHO Cells; D020746:Calcium Channels, L-Type / Q000502:physiology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004123:Dimethylamines / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D020746:Calcium Channels, L-Type; D004123:Dimethylamines; D051638:Ether-A-Go-Go Potassium Channels; D062554:NAV1.5 Voltage-Gated Sodium Channel; D026902:Potassium Channel Blockers; D011725:Pyridines; D017367:Selective Serotonin Reuptake Inhibitors; C000597675:(4-(3-methoxy-4-methylsulfanylphenoxy)pyridin-3-ylmethyl)dimethylamine; C568320:SCN5A protein, human