Noribogaine is a G-protein biased κ-opioid receptor agonist

Emeline L. Maillet, Nicolas Milon, Mari D. Heghinian, James Fishback, Stephan C Schuerer, Nandor Garamszegi, Deborah C Mash

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (K<inf>e</inf>) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC<inf>50</inf> = 9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC<inf>50</inf> of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6′-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

Original languageEnglish (US)
Pages (from-to)675-688
Number of pages14
JournalNeuropharmacology
Volume99
DOIs
StatePublished - Dec 1 2015

Fingerprint

Opioid Receptors
GTP-Binding Proteins
Dynorphins
Ibogaine
Arrestin
noribogaine
Opiate Alkaloids
Morphinans
Anxiety
kappa Opioid Receptor
mu Opioid Receptor
Brain
Guanosine Triphosphate
Opioid Analgesics
Inhibitory Concentration 50
Substance-Related Disorders
Analgesics
Binding Sites
Pharmacology
Ligands

Keywords

  • 18-MC
  • Addiction
  • Analgesia
  • Beta-arrestin pathway
  • Biased agonist
  • Computational simulation
  • Functional selectivity
  • G-protein pathway
  • Ibogaine
  • Kappa opioid receptor
  • Mu opioid receptor
  • Narcotic
  • Noribogaine

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Maillet, E. L., Milon, N., Heghinian, M. D., Fishback, J., Schuerer, S. C., Garamszegi, N., & Mash, D. C. (2015). Noribogaine is a G-protein biased κ-opioid receptor agonist. Neuropharmacology, 99, 675-688. https://doi.org/10.1016/j.neuropharm.2015.08.032

Noribogaine is a G-protein biased κ-opioid receptor agonist. / Maillet, Emeline L.; Milon, Nicolas; Heghinian, Mari D.; Fishback, James; Schuerer, Stephan C; Garamszegi, Nandor; Mash, Deborah C.

In: Neuropharmacology, Vol. 99, 01.12.2015, p. 675-688.

Research output: Contribution to journalArticle

Maillet, EL, Milon, N, Heghinian, MD, Fishback, J, Schuerer, SC, Garamszegi, N & Mash, DC 2015, 'Noribogaine is a G-protein biased κ-opioid receptor agonist', Neuropharmacology, vol. 99, pp. 675-688. https://doi.org/10.1016/j.neuropharm.2015.08.032
Maillet EL, Milon N, Heghinian MD, Fishback J, Schuerer SC, Garamszegi N et al. Noribogaine is a G-protein biased κ-opioid receptor agonist. Neuropharmacology. 2015 Dec 1;99:675-688. https://doi.org/10.1016/j.neuropharm.2015.08.032
Maillet, Emeline L. ; Milon, Nicolas ; Heghinian, Mari D. ; Fishback, James ; Schuerer, Stephan C ; Garamszegi, Nandor ; Mash, Deborah C. / Noribogaine is a G-protein biased κ-opioid receptor agonist. In: Neuropharmacology. 2015 ; Vol. 99. pp. 675-688.
@article{c04c99e9d4934da8829500fbd85965c0,
title = "Noribogaine is a G-protein biased κ-opioid receptor agonist",
abstract = "Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75{\%} as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50 = 9 μM) but only 12{\%} as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6′-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.",
keywords = "18-MC, Addiction, Analgesia, Beta-arrestin pathway, Biased agonist, Computational simulation, Functional selectivity, G-protein pathway, Ibogaine, Kappa opioid receptor, Mu opioid receptor, Narcotic, Noribogaine",
author = "Maillet, {Emeline L.} and Nicolas Milon and Heghinian, {Mari D.} and James Fishback and Schuerer, {Stephan C} and Nandor Garamszegi and Mash, {Deborah C}",
year = "2015",
month = "12",
day = "1",
doi = "10.1016/j.neuropharm.2015.08.032",
language = "English (US)",
volume = "99",
pages = "675--688",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Limited",

}

TY - JOUR

T1 - Noribogaine is a G-protein biased κ-opioid receptor agonist

AU - Maillet, Emeline L.

AU - Milon, Nicolas

AU - Heghinian, Mari D.

AU - Fishback, James

AU - Schuerer, Stephan C

AU - Garamszegi, Nandor

AU - Mash, Deborah C

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50 = 9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6′-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

AB - Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50 = 9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6′-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

KW - 18-MC

KW - Addiction

KW - Analgesia

KW - Beta-arrestin pathway

KW - Biased agonist

KW - Computational simulation

KW - Functional selectivity

KW - G-protein pathway

KW - Ibogaine

KW - Kappa opioid receptor

KW - Mu opioid receptor

KW - Narcotic

KW - Noribogaine

UR - http://www.scopus.com/inward/record.url?scp=84941751924&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941751924&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2015.08.032

DO - 10.1016/j.neuropharm.2015.08.032

M3 - Article

C2 - 26302653

AN - SCOPUS:84941751924

VL - 99

SP - 675

EP - 688

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -