hERG Blockade by Iboga Alkaloids

Kenneth Alper, Rong Bai, Nian Liu, Steven J. Fowler, Xi Ping Huang, Silvia G. Priori, Yanfei Ruan

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 (Ki) 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.

Original languageEnglish
Pages (from-to)14-22
Number of pages9
JournalCardiovascular Toxicology
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

Fingerprint

Ibogaine
Tabernaemontana
Alkaloids
Inhibitory Concentration 50
Clamping devices
Metabolites
Torsades de Pointes
Pharmaceutical Preparations
Self Administration
HEK293 Cells
Patch-Clamp Techniques
Substitution reactions
Skeleton
Half-Life
Cardiac Arrhythmias
Eating
Electric potential
voacangine
noribogaine

Keywords

  • 18-Methoxycoronaridine (18-MC)
  • hERG
  • Iboga alkaloid
  • Ibogaine
  • Noribogaine
  • Toxicology

ASJC Scopus subject areas

  • Toxicology
  • Cardiology and Cardiovascular Medicine
  • Molecular Biology

Cite this

Alper, K., Bai, R., Liu, N., Fowler, S. J., Huang, X. P., Priori, S. G., & Ruan, Y. (2016). hERG Blockade by Iboga Alkaloids. Cardiovascular Toxicology, 16(1), 14-22. https://doi.org/10.1007/s12012-015-9311-5

hERG Blockade by Iboga Alkaloids. / Alper, Kenneth; Bai, Rong; Liu, Nian; Fowler, Steven J.; Huang, Xi Ping; Priori, Silvia G.; Ruan, Yanfei.

In: Cardiovascular Toxicology, Vol. 16, No. 1, 01.01.2016, p. 14-22.

Research output: Contribution to journalArticle

Alper, K, Bai, R, Liu, N, Fowler, SJ, Huang, XP, Priori, SG & Ruan, Y 2016, 'hERG Blockade by Iboga Alkaloids', Cardiovascular Toxicology, vol. 16, no. 1, pp. 14-22. https://doi.org/10.1007/s12012-015-9311-5
Alper K, Bai R, Liu N, Fowler SJ, Huang XP, Priori SG et al. hERG Blockade by Iboga Alkaloids. Cardiovascular Toxicology. 2016 Jan 1;16(1):14-22. https://doi.org/10.1007/s12012-015-9311-5
Alper, Kenneth ; Bai, Rong ; Liu, Nian ; Fowler, Steven J. ; Huang, Xi Ping ; Priori, Silvia G. ; Ruan, Yanfei. / hERG Blockade by Iboga Alkaloids. In: Cardiovascular Toxicology. 2016 ; Vol. 16, No. 1. pp. 14-22.
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