Noribogaine

Noribogaine
Clinical data
Other names12-Hydroxyibogamine; Ibogamin-12-ol; O-desmethylibogaine; (-)-Noribogaine;
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: Unscheduled (but still a Schedule I analogue due to being a main metabolite of C-I ibogaine)
Identifiers
  • (1R,15R,17S,18S)-17-ethyl-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4(9),5,7-tetraen-7-ol
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC19H24N2O
Molar mass296.414 g·mol−1
3D model (JSmol)
  • CC[C@H]1C[C@@H]2C[C@@H]3[C@H]1N(C2)CCC4=C3NC5=C4C=C(C=C5)O
  • InChI=1S/C19H24N2O/c1-2-12-7-11-8-16-18-14(5-6-21(10-11)19(12)16)15-9-13(22)3-4-17(15)20-18/h3-4,9,11-12,16,19-20,22H,2,5-8,10H2,1H3/t11-,12+,16+,19+/m1/s1 checkY
  • Key:RAUCDOKTMDOIPF-RYRUWHOVSA-N checkY
 ☒NcheckY (what is this?)  (verify)

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

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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

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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.[13] With an IC50 value of 1 μM, it can be regarded as an antagonist of the latter pathway.[13]

The β-arrestin signaling pathway is hypothesized to be responsible for the anxiogenic, dysphoric, or anhedonic effects of KOR activation.[14] Attenuation of the β-arrestin pathway by noribogaine may be the reason for the absence of these aversive effects,[13] while retaining analgesic and antiaddictive properties. This biased KOR activity makes it stand out from the other iboga alkaloids like ibogaine and the derivative 18-methoxycoronaridine (18-MC).[13]

Benzofuran analog

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In 2024, a synthetic benzofuran analog (oxa-noribogaine) was reported that is devoid of the pro-arrhythmic side effect. It has analgesic effects as a potent (atypical) kappa-opioid receptor partial agonist and, opposed to standard KOR agonists, is characterized by the absence of pro-depressant effects. It induces a robust KOR-dependent increase in GDNF protein levels in the ventral tegmental area and medial prefrontal cortex. After a single dose or short-term treatment, oxa-noribogaine induces long-lasting suppression of opioid drug seeking in rodent relapse models. It also counteracts persistent opioid-induced hyperalgesia.[15]

See also

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References

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  1. ^ Mash DC, Ameer B, Prou D, Howes JF, Maillet EL (2016). "Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents". J. Psychopharmacol. (Oxford). 30 (7): 688–97. doi:10.1177/0269881116641331. PMID 27044509. S2CID 40776971.
  2. ^ Glick SD, Maisonneuve IS (May 1998). "Mechanisms of antiaddictive actions of ibogaine". Annals of the New York Academy of Sciences. 844 (1): 214–26. Bibcode:1998NYASA.844..214G. doi:10.1111/j.1749-6632.1998.tb08237.x. PMID 9668680. S2CID 11416176.
  3. ^ Baumann MH, Pablo J, Ali SF, Rothman RB, Mash DC (2001). "Comparative neuropharmacology of ibogaine and its O-desmethyl metabolite, noribogaine". The Alkaloids: Chemistry and Biology. 56: 79–113. doi:10.1016/S0099-9598(01)56009-5. PMID 11705118.
  4. ^ Kubiliene A, Marksiene R, Kazlauskas S, Sadauskiene I, Razukas A, Ivanov L (2008). "Acute toxicity of ibogaine and noribogaine". Medicina. 44 (12): 984–8. doi:10.3390/medicina44120123. PMID 19142057.
  5. ^ Max M. Houck (26 January 2015). Forensic Chemistry. Elsevier Science. pp. 164–. ISBN 978-0-12-800624-5.
  6. ^ Baumann MH, Rothman RB, Pablo JP, Mash DC (May 2001). "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. PMID 11303040.
  7. ^ Paul Gahlinger (30 December 2003). Illegal Drugs. Penguin Publishing Group. pp. 304–. ISBN 978-1-4406-5024-6.
  8. ^ Alper KR, Glick SD (2001). Ibogaine: Proceedings from the First International Conference. Gulf Professional Publishing. pp. 107–. ISBN 978-0-12-053206-3.
  9. ^ Donald G. Barceloux (20 March 2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. pp. 869–. ISBN 978-0-471-72760-6.
  10. ^ Pearl SM, Herrick-Davis K, Teitler M, Glick SD (March 1995). "Radioligand-binding study of noribogaine, a likely metabolite of ibogaine". Brain Research. 675 (1–2): 342–344. doi:10.1016/0006-8993(95)00123-8. PMID 7796150. S2CID 28001919.
  11. ^ Alper K, Bai R, Liu N, Fowler SJ, Huang XP, Priori SG, Ruan Y (2016). "hERG Blockade by Iboga Alkaloids". Cardiovasc. Toxicol. 16 (1): 14–22. doi:10.1007/s12012-015-9311-5. PMID 25636206. S2CID 16071274.
  12. ^ Litjens RP, Brunt TM (2016). "How toxic is ibogaine?". Clin Toxicol. 54 (4): 297–302. doi:10.3109/15563650.2016.1138226. PMID 26807959. S2CID 7026570.
  13. ^ a b c d e Maillet EL, Milon N, Heghinian MD, Fishback J, Schürer SC, Garamszegi N, Mash DC (2015). "Noribogaine is a G-protein biased κ-opioid receptor agonist". Neuropharmacology. 99: 675–88. doi:10.1016/j.neuropharm.2015.08.032. PMID 26302653.
  14. ^ Ehrich JM, Messinger DI, Knakal CR, Kuhar JR, Schattauer SS, Bruchas MR, Zweifel LS, Kieffer BL, Phillips PE, Chavkin C (2015). "Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons". J. Neurosci. 35 (37): 12917–31. doi:10.1523/JNEUROSCI.2444-15.2015. PMC 4571610. PMID 26377476.
  15. ^ Havel V, Kruegel AC, Bechand B, et al. (2024). "Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models". Nat Commun. 15 (1): 8118. doi:10.1038/s41467-024-51856-y. PMC 11415492. PMID 39304653.
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