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.

Involvement of Activated Brain Stress Responsive Systems in Excessive and “Relapse” Alcohol Drinking in Rodent Models: Implications for Therapeutics

“…Our study is in line with growing research into the development of biased KOP-r ligands for anti-addictive compounds [Maillet et al, 2015;White et al, 2015;Brust et al, 2016;Townsend et al, 2017].…”

“…Recently, there is rapidly growing research into the identification of functionally selective (biased) KOP-r full agonists or partial agonists for the development of anti-addictive compounds [Maillet et al, 2015;Simonson et al, 2015;White et al, 2015;Brust et al, 2016;Schattauer et al, 2017;Townsend et al, 2017;Zhou et al, 2017a]. For a good example, Mesyl Salvinorin B (MSB), an analogue of salvinorin A, is a potent KOP-r full agonist with fewer side effects (sedation and dysphoria) compared to other "classic" KOP-r agonists [Simonson et al, 2015;Zhou et al, 2017a].…”

“…Therefore, our new data that the KOP-r full agonist MSB reduces, rather than triggers, relapse-like drinking, presents a scenario that seems opposite to the results using classic KOP-r agonists. After chronic excessive alcohol consumption, however, the endogenous dynorphin (a G-protein and beta-arrestin dependent agonist [Maillet et al, 2015;White et al, 2015]) and KOP-r systems are activated in several neuronal structures. Either the increased release of dynorphin [Marinelli et al, 2006] or enhanced KOP-r activity produces sedation, dysphoria, anxiety-and depression-like behaviors that may drive excessive and "relapse" drinking [Tunstall et al, 2017].…”

Modulation of neuroinflammation and pathology in the 5XFAD mouse model of Alzheimer's disease using a biased and selective beta-1 adrenergic receptor partial agonist

“…At the same time, ADRB1 activation would stimulate recruitment of β-arrestin to the receptor, leading to receptor desensitization (Pierce and Lefkowitz 2001; Freedman and Lefkowitz 1996; Zhang et al 1997). However, it has become clear that agonists can show biased activation of signaling pathways in an agonist-specific manner (Rajagopal et al 2010; Allen et al 2011; Violin and Lefkowitz 2007; Maillet et al 2015). In the case of xamoterol, it selectively activated the cAMP pathway while maintaining minimal (~10%) activity on the β-arrestin pathway.…”

Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents

“…Place approach infers a hedonic valence for the unique environment cues of the compartment. Initial side preferences/bias (1) was used to determine which of the two compartments would be paired with oral gavage dose of noribogaine, and (2) and (3) biased agonist of the kappa opioid receptor (Maillet et al, 2015). The effects of prototypical G-protein biased agonism at the kappa receptors are believed to encompass analgesia not associated with dysphoria and to be useful in the treatment of addiction (Chavkin, 2011).…”