Noribogaine (actually O-desmethylibogaine), or 12-hydroxyibogamine, is the principal psychoactive metabolite of the

oneirogen An oneirogen, from the Greek ὄνειρος ''óneiros'' meaning "dream" and ''gen'' "to create", is that which produces or enhances dreamlike states of consciousness. This is characterized by an immersive dream state similar to REM sleep, which ...

ibogaine Ibogaine is a naturally occurring psychoactive substance found in plants in the family Apocynaceae such as '' Tabernanthe iboga'', '' Voacanga africana'', and '' Tabernaemontana undulata''. It is a psychedelic with dissociative properties. Pre ...

. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as ''

Tabernanthe iboga ''Tabernanthe iboga'' (iboga) is an evergreen rainforest shrub native to Central Africa. A member of the Apocynaceae family indigenous to Gabon, the Democratic Republic of Congo, and the Republic of Congo, it is cultivated across Central Africa ...

''.

Pharmacology

Noribogaine is a potent

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to incre ...

, but does not affect the

reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the Synapse, pre-synaptic neuron at a synapse) or glial cell after it has performed its function of ...

of dopamine. Unlike ibogaine, noribogaine does not bind to the

sigma-2 receptor The sigma-2 receptor (σ2R) is a sigma receptor subtype that has attracted attention due to its involvement in diseases such as cancer and neurological diseases. It is currently under investigation for its potential diagnostic and therapeutic use ...

. Similarly to ibogaine, noribogaine acts as a weak

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce ...

and binds to

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin ...

s. It has greater affinity for each of the opioid receptors than does ibogaine. Noribogaine is a

hERG hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...

inhibitor and appears at least as potent as ibogaine. The inhibition of the hERG

potassium channel Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of c ...

delays the

repolarization In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarizat ...

cardiac action potential The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins c ...

s, resulting in QT interval

prolongation In music theory, prolongation is the process in tonal music through which a pitch, interval, or consonant triad is considered to govern spans of music when not physically sounding. It is a central principle in the music-analytic methodology o ...

and, subsequently, in arrhythmias and sudden

cardiac arrest Cardiac arrest is when the heart suddenly and unexpectedly stops beating. It is a medical emergency that, without immediate medical intervention, will result in sudden cardiac death within minutes. Cardiopulmonary resuscitation (CPR) and poss ...

κ-Opioid receptor

Noribogaine has been determined to act as a

biased agonist Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand (biochemistry), ligand-dependent selectivity for certain signal transduction pathway ...

of the

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...

(KOR). It activates the

G protein G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their a ...

(GDP-GTP exchange) signaling pathway with 75% the efficacy of

dynorphin A Dynorphin A is a dynorphin, an endogenous opioid peptide with the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys. Dynorphin A1–8 is a truncated form of dynorphin A with the amino acid sequence: Tyr-Gly-Gly-Phe-Leu-Ar ...

( EC₅₀ = 9 μM), but it is only 12% as efficacious at activating the β-arrestin pathway. Moreover, due to its very low efficacy on the β-arrestin pathway, noribogaine blocked dynorphin A activation of the pathway ( IC₅₀ = 1 μM) and hence functioned as an antagonist of it. The β-arrestin pathway is thought to be responsible for the dysphoric and aversive effects of KOR activation, and its lack of activation by noribogaine may be the reason for the lack of dysphoric effects of the drug. This biased agonist/antagonist action of noribogaine at the KOR is unique to it relative to other

iboga alkaloid Iboga alkaloids are alkaloid constituents of ''Tabernanthe iboga''. Iboga alkaloids include ibogaine, tabernanthine, coronaridine, voacangine, ibogamine, and harmaline, among others. Noribogaine is a major active metabolite An active metabolite is ...

s and related compounds such as

and 18-methoxycoronaridine (18-MC). Moreover, it has been hypothesized that it may give noribogaine unique properties such that it may have the analgesic and antiaddictive effects of KOR agonists without the anxiogenic, dysphoric, or anhedonic effects that are typical of them.

References

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Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms ...

, titlestyle = background:#ccccff , list1 = {{Ionotropic glutamate receptor modulators {{Monoamine reuptake inhibitors {{Opioid receptor modulators {{Serotonin receptor modulators {{Sigma receptor modulators Biased ligands Iboga HERG blocker Delta-opioid receptor antagonists Kappa-opioid receptor agonists Kappa-opioid receptor antagonists Mu-opioid receptor antagonists NMDA receptor antagonists Opioids Phenols Serotonin reuptake inhibitors

Pharmacology

κ-Opioid receptor

See also

References