hERG Blockade by Iboga Alkaloids.

Ibogaine, a compound used to treat addiction, can cause dangerous heart rhythm problems by blocking hERG potassium channels. This study measured how strongly several iboga alkaloids block hERG channels in human cells. Ibogaine and its metabolite noribogaine blocked hERG channels with IC50 values around 2-4 µM, while 18-methoxycoronaridine (18-MC), a synthetic derivative, showed much weaker blockade (IC50 >50 µM). Although 18-MC bound to hERG channels with similar affinity as other compounds, it produced substantially less channel blockade. These findings suggest that 18-MC may have a safer cardiac profile than ibogaine, and that the structural differences among iboga alkaloids offer a useful model for studying hERG channel biology.

Study at a glance

Abstract

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.