hERG Blockade by Iboga Alkaloids

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.

Anti-addiction Drug Ibogaine Prolongs the Action Potential in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…This observation goes along with noribogaine’s inhibitory action on hERG potassium channels (IC 50  = 3 µM: Fig. 2; [17]), which very closely resembles hERG inhibition by ibogaine [13, 14, 17]. It further provides an explanation for the delayed incidence of cardiac adverse events, which may occur even several days after ibogaine intake.

Fig.

…”

“…Up to now, the inhibition of currents through heterologously expressed hERG channels by ibogaine (IC 50 value, drug concentration needed for half-maximum inhibition = 3–4 µM [13, 14, 17]) remains the sole experimental evidence for the drug’s proarrhythmic potential in humans; data on human cardiomyocytes are still lacking. Moreover, two observations have cast reasonable doubts on ibogaine’s cardiotoxic effects: first, although hERG channel inhibition should retard AP repolarization, the drug significantly shortens AP duration in guinea pig ventricular cardiomyocytes [14]), a well-established model system for human myocytes.…”

“…Recently, alarming reports of life-threatening cardiac arrhythmias and sudden death cases [ 4 – 12 ], temporally associated with the ingestion of ibogaine, have accumulated. We [ 13 – 16 ] and others [ 17 ] hypothesized that these were related to the drug’s propensity to block human ether-a-go-go-related gene (hERG) potassium channels in the heart, which can result in retardation of ventricular action potential (AP) repolarization and prolongation of the QT interval in the electrocardiogram (ECG) [ 18 ]. QT prolongation—indeed observed in people after ibogaine intake (e.g.…”

hERG Channel Blocking Ipecac Alkaloids Identified by Combined In Silico – In Vitro Screening

“…A special focus was given to plants containing alkaloids with reported cardiac side effects. Several studies have shown the hERG channel blocking potential of these nitrogen-containing compounds [6][7][8]25]. Recently, we reported on the development and experimental validation of several ligand-based hERG 3D-pharmacophore models [9].…”

“…Supporting information available online at http://www.thieme-connect.de/products prospectively and retrospectively [4][5][6][7][8]. In this view, in vitro/in vivo assays can be combined with in silico approaches allowing for the fast prediction of hERG channel blocking and providing insights into the ligand-target interaction at a molecular level [9][10][11][12].…”