title: 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.
authors: Departments of Psychiatry and Neurology, New York University School of Medicine, New York, NY, 10016, USA.
authors: Kenneth
authors: K
authors: Alper
authors: National Clinical Research Center for Cardiovascular Diseases and Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing, 100029, China.
authors: Rong
authors: R
authors: Bai
authors: National Clinical Research Center for Cardiovascular Diseases and Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing, 100029, China.
authors: Nian
authors: N
authors: Liu
authors: Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
authors: Steven J
authors: SJ
authors: Fowler
authors: National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors: Xi-Ping
authors: XP
authors: Huang
authors: Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
authors: Silvia G
authors: SG
authors: Priori
authors: National Clinical Research Center for Cardiovascular Diseases and Department of Cardiology, Beijing An Zhen Hospital, Capital Medical University, Beijing, 100029, China. ruanyanfei@hotmail.com.|Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA. ruanyanfei@hotmail.com.
authors: Yanfei
authors: Y
authors: Ruan
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D018408:Patch-Clamp Techniques; D010936:Plant Extracts / Q000737:chemistry; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D030014:Tabernaemontana / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D051638:Ether-A-Go-Go Potassium Channels; D010936:Plant Extracts; D026902:Potassium Channel Blockers; D007050:Ibogaine; C012098:voacangine; C094385:noribogaine; C103345:18-methoxycoronaridine
keywords: 18-Methoxycoronaridine (18-MC); Iboga alkaloid; Ibogaine; Noribogaine; Toxicology; hERG