Mechanism of hERG channel block by the psychoactive indole alkaloid ibogaine.
The Journal of pharmacology and experimental therapeutics February 1, 2014 Patrick Thurner, Anna Stary-Weinzinger, Hend Gafar et al. 41 citations
Ibogaine, a psychoactive alkaloid used to treat addiction, can cause dangerous heart rhythm problems by blocking hERG potassium channels. Experiments on mammalian kidney cells expressing hERG channels showed that block occurred from either side of the cell membrane and depended on pH. Block happened only when channels were activated, not when resting. Stronger depolarizations increased block speed and extent. The drug shifted channel activation and inactivation to more negative voltages, slowed deactivation, and accelerated inactivation. Mutations Y652A and F656A reduced ibogaine's potency, but an inactivation-deficient mutant remained sensitive. Molecular docking suggested binding inside the channel cavity regardless of ibogaine's protonation state. Kinetic modeling indicated preferential binding to open and inactivated states.