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.
authors: DemeRx, Inc., R&D Laboratory, Life Science & Technology Park, 1951 NW 7th Ave, Suite 300, Miami, FL 33136, USA. Electronic address: emaillet@demerx.us.
authors: Emeline L
authors: EL
authors: Maillet
authors: DemeRx, Inc., R&D Laboratory, Life Science & Technology Park, 1951 NW 7th Ave, Suite 300, Miami, FL 33136, USA.
authors: Nicolas
authors: N
authors: Milon
authors: DemeRx, Inc., R&D Laboratory, Life Science & Technology Park, 1951 NW 7th Ave, Suite 300, Miami, FL 33136, USA.
authors: Mari D
authors: MD
authors: Heghinian
authors: DemeRx, Inc., R&D Laboratory, Life Science & Technology Park, 1951 NW 7th Ave, Suite 300, Miami, FL 33136, USA.
authors: James
authors: J
authors: Fishback
authors: University of Miami, Center for Computational Science, 1320 S, Dixie Highway, Gables One Tower #600.H, Locator Code 2965, Coral Gables, FL 33146-2926, USA; Miller School of Medicine, Molecular and Cellular Pharmacology, 14th Street CRB 650 (M-857), Miami, FL 33136, USA.
authors: Stephan C
authors: SC
authors: Schürer
authors: DemeRx, Inc., R&D Laboratory, Life Science & Technology Park, 1951 NW 7th Ave, Suite 300, Miami, FL 33136, USA.
authors: Nandor
authors: N
authors: Garamszegi
authors: DemeRx, Inc., R&D Laboratory, Life Science & Technology Park, 1951 NW 7th Ave, Suite 300, Miami, FL 33136, USA.
authors: Deborah C
authors: DC
authors: Mash
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D003198:Computer Simulation; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D004399:Dynorphins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007050:Ibogaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009019:Morphinans / Q000378:metabolism; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019966:Substance-Related Disorders / Q000517:prevention & control; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; D019390:Arrestins; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D000071557:beta-Arrestins; D007050:Ibogaine; D004399:Dynorphins; C094385:noribogaine; D019204:GTP-Binding Proteins
keywords: 18-MC; 18-Methoxycoronaridine (PubMed CID: 15479177); Addiction; Analgesia; Beta-arrestin pathway; Biased agonist; Computational simulation; DAMGO (PubChem CID: 44279043); Functional selectivity; G-protein pathway; Ibogaine; Ibogaine (PubChem CID: 363272); Kappa opioid receptor; Mu opioid receptor; Naloxone (PubChem CID: 5464092); Narcotic; Nor-binaltorphimine (nor-BNI) (PubChem CID: 5480230); Noribogaine; Noribogaine hydrochloride (PubChem CID: 457966); U69,593 (PubChem CID: 105104); dynorphin A (PubChem CID: 16133805); morphine (PubChem CID: 5288826); nalmefene (PubChem CID: 5388881)