Noribogaine

Pharmacodynamics

Noribogaine has been determined to act as a biased agonist of the κ-opioid receptor (KOR).^[12] It activates the G protein (GDP-GTP exchange) signaling pathway with 75% the efficacy of dynorphin A (EC₅₀ = 9 Î¼M), but it is only 12% as efficacious at activating the β-arrestin pathway.^[12] With an IC₅₀ value of 1 Î¼M, it can be regarded as an antagonist of the latter pathway.^[12]

The β-arrestin signaling pathway is hypothesized to be responsible for the anxiogenic, dysphoric, or anhedonic effects of KOR activation.^[33] Attenuation of the β-arrestin pathway by noribogaine may be the reason for the absence of these aversive effects,^[12] 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).^[12] Some other examples of atypical or biased KOR agonists include RB-64, 6'-GNTI, herkinorin, and nalfurafine.

Noribogaine is a potent serotonin reuptake inhibitor,^[13] but does not affect the reuptake of dopamine.^[34] Unlike ibogaine, noribogaine does not bind to the sigma σ₂ receptor.^[35][36] Similarly to ibogaine, noribogaine acts as a weak NMDA receptor antagonist and binds to opioid receptors.^[37] It has greater affinity for each of the opioid receptors than does ibogaine.^[38] Noribogaine has been reported to be a low-efficacy serotonin releasing agent, although findings are conflicting and other studies have found that it is inactive as a serotonin releasing agent.^[31][30] As with ibogaine, noribogaine is inactive as an agonist of the serotonin 5-HT_2A receptor.^[14][29]

Noribogaine is a hERG inhibitor and appears at least as potent as ibogaine.^[39] 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.^[40]

Ibogaine and the structurally related hallucinogen harmaline are tremorigenic, whereas noribogaine is not or is much less so.^{[15][11][41][42]}

Noribogaine, but not ibogaine, produces potent psychoplastogenic effects in vitro in preclinical research.^{[43][44][14][15][31][16]} This can be blocked by the serotonin 5-HT_2A receptor antagonist ketanserin, by the mTOR inhibitor rapamycin, and by a TrkB antagonist.^[43][16]

Pharmacokinetics

Noribogaine is highly lipophilic and shows high brain penetration in rodents.^[10][3]

The elimination half-life of noribogaine is 24 to 50 hours.^[3][1][2]

Analogues

Analogues of noribogaine include ibogaine, ibogamine, desethylibogamine, voacangine, tabernanthine, coronaridine, oxa-noribogaine, and GM-3009, among others.