Mechanism of hERG channel block by the psychoactive indole alkaloid ibogaine.
Patrick Thurner, Anna Stary-Weinzinger, Hend Gafar, Vaibhavkumar S Gawali, Oliver Kudlacek, Juergen Zezula, Karlheinz Hilber, Stefan Boehm, Walter Sandtner, Xaver Koenig
Journal of Pharmacology and Experimental Therapeutics February 1, 2014 DOI: 10.1124/jpet.113.209643 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental laboratory study Peer reviewed |
|---|---|
| Population | Mammalian kidney tsA-201 cells heterologously expressing hERG channels |
| Intervention | Ibogaine |
| Topics | Ibogaine |
| Keywords | Cardiotoxicity Herg channel mechanism |
| Citations | 41 |
| Key findings | Ibogaine blocks hERG potassium channels by binding preferentially to open and inactivated states from the cytosolic side, with block dependent on activation and pH. |
Abstract
Ibogaine is a psychoactive indole alkaloid. Its use as an antiaddictive agent has been accompanied by QT prolongation and cardiac arrhythmias, which are most likely caused by human ether a go-go-related gene (hERG) potassium channel inhibition. Therefore, we studied in detail the interaction of ibogaine with hERG channels heterologously expressed in mammalian kidney tsA-201 cells. Currents through hERG channels were blocked regardless of whether ibogaine was applied via the extracellular or intracellular solution. The extent of inhibition was determined by the relative pH values. Block occurred during activation of the channels and was not observed for resting channels. With increasing depolarizations, ibogaine block grew and developed faster. Steady-state activation and inactivation of the channel were shifted to more negative potentials. Deactivation was slowed, whereas inactivation was accelerated. Mutations in the binding site reported for other hERG channel blockers (Y652A and F656A) reduced the potency of ibogaine, whereas an inactivation-deficient double mutant (G628C/S631C) was as sensitive as wild-type channels. Molecular drug docking indicated binding within the inner cavity of the channel independently of the protonation of ibogaine. Experimental current traces were fit to a kinetic model of hERG channel gating, revealing preferential binding of ibogaine to the open and inactivated state. Taken together, these findings show that ibogaine blocks hERG channels from the cytosolic side either in its charged form alone or in company with its uncharged form and alters the currents by changing the relative contribution of channel states over time.
Comparable studies
Other experimental studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter. In vitro (SERT) | 2007 | Laboratory study | |
| Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. | 1992 | Laboratory study | |
| The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters. | 2012 | Experimental study | |
| Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. | 1995 | Experimental study | |
| Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. | 1995 | Laboratory study |
Citations in the library
Cited by 22
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation Molecules January 29, 2015
- Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients. Clinical Pharmacology in Drug Development November 1, 2016
- DARK Classics in Chemical Neuroscience: Ibogaine ACS Chemical Neuroscience September 14, 2018
- Safety of ibogaine administration in detoxification of opioid-dependent individuals: a descriptive open-label observational study. Addiction 2022
and 17 more in the library
Cites 10
- The ibogaine medical subculture. Journal of Ethnopharmacology January 4, 2008
- Medication Development of Ibogaine as a Pharmacotherapy for Drug Dependencea. Annals of the New York Academy of Sciences May 1, 1998
- Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review. Human & Experimental Toxicology March 1, 2008
- Fatalities temporally associated with the ingestion of ibogaine. Journal of Forensic Sciences March 1, 2012
- Anti-addiction drug ibogaine inhibits hERG channels: a cardiac arrhythmia risk. Addiction Biology March 1, 2014
and 5 more in the library