Noribogaine Explained

Noribogaine (actually O-desmethylibogaine), or 12-hydroxyibogamine, is the principal psychoactive metabolite of the oneirogen ibogaine. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as Tabernanthe iboga.[1] [2] [3] [4]

Pharmacology

Noribogaine is a potent serotonin reuptake inhibitor,[5] but does not affect the reuptake of dopamine.[6] Unlike ibogaine, noribogaine does not bind to the sigma-2 receptor.[7] [8] Similarly to ibogaine, noribogaine acts as a weak NMDA receptor antagonist and binds to opioid receptors.[9] It has greater affinity for each of the opioid receptors than does ibogaine.[10]

Noribogaine is a hERG inhibitor and appears at least as potent as ibogaine.[11] The inhibition of the hERG potassium channel delays the repolarization of cardiac action potentials, resulting in QT interval prolongation and, subsequently, in arrhythmias and sudden cardiac arrest.[12]

κ-Opioid receptor

Noribogaine has been determined to act as a biased agonist of the κ-opioid receptor (KOR).[13] It activates the G protein (GDP-GTP exchange) signaling pathway with 75% the efficacy of dynorphin A (EC50 = 9 μM), but it is only 12% as efficacious at activating the β-arrestin pathway. Moreover, due to its very low efficacy on the β-arrestin pathway, noribogaine blocked dynorphin A activation of the pathway (IC50 = 1 μM) and hence functioned as an antagonist of it.

The β-arrestin pathway is thought to be responsible for the dysphoric and aversive effects of KOR activation,[14] and its lack of activation by noribogaine may be the reason for the lack of dysphoric effects of the drug. This biased agonist/antagonist action of noribogaine at the KOR is unique to it relative to other iboga alkaloids and related compounds such as ibogaine and 18-methoxycoronaridine (18-MC). Moreover, it has been hypothesized that it may give noribogaine unique properties such that it may have the analgesic and antiaddictive effects of KOR agonists without the anxiogenic, dysphoric, or anhedonic effects that are typical of them.

See also

Notes and References

  1. Mash DC, Ameer B, Prou D, Howes JF, Maillet EL . Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents . J. Psychopharmacol. (Oxford) . 30 . 7 . 688–97 . 2016 . 27044509 . 10.1177/0269881116641331 . 40776971 .
  2. Glick SD, Maisonneuve IS . Mechanisms of antiaddictive actions of ibogaine . Annals of the New York Academy of Sciences . 844 . 214–26 . May 1998 . 1 . 9668680 . 10.1111/j.1749-6632.1998.tb08237.x. 1998NYASA.844..214G . 11416176 .
  3. Baumann MH, Pablo J, Ali SF, Rothman RB, Mash DC . Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine . The Alkaloids: Chemistry and Biology . 56 . 79–113 . 2001 . 11705118 . 10.1016/S0099-9598(01)56009-5.
  4. Kubiliene A, Marksiene R, Kazlauskas S, Sadauskiene I, Razukas A, Ivanov L . Acute toxicity of ibogaine and noribogaine . Medicina . 44 . 12 . 984–8 . 2008 . 10.3390/medicina44120123 . 19142057 . free .
  5. Book: Max M. Houck. Forensic Chemistry. 26 January 2015. Elsevier Science. 978-0-12-800624-5. 164–.
  6. Baumann MH, Rothman RB, Pablo JP, Mash DC . In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats . The Journal of Pharmacology and Experimental Therapeutics . 297 . 2 . 531–539 . May 2001 . 11303040 .
  7. Book: Paul Gahlinger. Illegal Drugs. 30 December 2003. Penguin Publishing Group. 978-1-4406-5024-6. 304–.
  8. Book: Alper KR, Glick SD . Ibogaine: Proceedings from the First International Conference. 2001. Gulf Professional Publishing. 978-0-12-053206-3. 107–.
  9. Book: Donald G. Barceloux. Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. 20 March 2012. John Wiley & Sons. 978-0-471-72760-6. 869–.
  10. Pearl SM, Herrick-Davis K, Teitler M, Glick SD . Radioligand-binding study of noribogaine, a likely metabolite of ibogaine . Brain Research . 675 . 1–2 . 342–344 . March 1995 . 7796150 . 10.1016/0006-8993(95)00123-8 . 28001919 .
  11. Alper K, Bai R, Liu N, Fowler SJ, Huang XP, Priori SG, Ruan Y . hERG Blockade by Iboga Alkaloids . Cardiovasc. Toxicol. . 16 . 1 . 14–22 . 2016 . 25636206 . 10.1007/s12012-015-9311-5 . 16071274 .
  12. Litjens RP, Brunt TM . How toxic is ibogaine? . Clin Toxicol . 54 . 4 . 297–302 . 2016 . 26807959 . 10.3109/15563650.2016.1138226 . 7026570 .
  13. Maillet EL, Milon N, Heghinian MD, Fishback J, Schürer SC, Garamszegi N, Mash DC . Noribogaine is a G-protein biased κ-opioid receptor agonist . Neuropharmacology . 99 . 675–88 . 2015 . 26302653 . 10.1016/j.neuropharm.2015.08.032 . free .
  14. Ehrich JM, Messinger DI, Knakal CR, Kuhar JR, Schattauer SS, Bruchas MR, Zweifel LS, Kieffer BL, Phillips PE, Chavkin C . Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons . J. Neurosci. . 35 . 37 . 12917–31 . 2015 . 26377476 . 10.1523/JNEUROSCI.2444-15.2015 . 4571610 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Noribogaine".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.