18-Methoxycoronaridine (18-MC; developmental code name MM-110), also known as zolunicant (), is a derivative of

ibogaine Ibogaine is a psychoactive indole alkaloid derived from plants such as '' Tabernanthe iboga'', characterized by hallucinogenic and oneirogenic effects. Traditionally used by Central African foragers, it has undergone controversial research ...

invented in 1996 by the research team around the pharmacologist Stanley D. Glick from the

Albany Medical College Albany Medical College (AMC) is a Private university, private medical school in Albany, New York. It was founded in 1839 by Alden March and James H. Armsby and is one of the oldest medical schools in the nation. The college is part of the Albany Me ...

and the chemists Upul K. Bandarage and Martin E. Kuehne from the

University of Vermont The University of Vermont and State Agricultural College, commonly referred to as the University of Vermont (UVM), is a Public university, public Land-grant university, land-grant research university in Burlington, Vermont, United States. Foun ...

. In animal studies it has proven to be effective at reducing self-administration of

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

and

sucrose Sucrose, a disaccharide, is a sugar composed of glucose and fructose subunits. It is produced naturally in plants and is the main constituent of white sugar. It has the molecular formula . For human consumption, sucrose is extracted and refined ...

. It has also been shown to produce

anorectic An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

effects in obese rats, most likely due to the same actions on the reward system which underlie its anti-addictive effects against drug addiction. 18-MC was in the early stages of human testing by the California-based drug development company Savant HWP before being acquired by MindMed, a Canadian pharmaceutical company newly listed on the NASDAQ in April 2021.Mindmed Acquires Opioid Addiction Drug Candidate Based on the Natural Psychedelic Ibogaine
newswire.ca September 16, 2019.Albany Med scientist closer to addiction drug success
timesunion.com June 27, 2014. In 2002 the research team began raising funds for human trials, but were unable to secure the estimated $5 million needed. In 2010, Obiter Research, a chemical manufacturer in

Champaign, Illinois Champaign ( ) is a city in Champaign County, Illinois, United States. The population was 88,302 at the 2020 census. It is the List of municipalities in Illinois, tenth-most populous municipality in Illinois and the fourth most populous city in ...

, signed a patent license with

and the

, allowing them the right to synthesize and market 18-MC and other congeners. In 2012 the

National Institute on Drug Abuse The National Institute on Drug Abuse (NIDA) is a United States federal government research institute whose mission is to "advance science on the causes and consequences of drug use and addiction and to apply that knowledge to improve individual ...

gave a $6.5 million grant to Savant HWP for human trials. In 2017 it went into Phase-II trials in Brazil for treatment of

Leishmaniasis Leishmaniasis is a wide array of clinical manifestations caused by protozoal parasites of the Trypanosomatida genus ''Leishmania''. It is generally spread through the bite of Phlebotominae, phlebotomine Sandfly, sandflies, ''Phlebotomus'' an ...

at the

Evandro Chagas Institute The Evandro Chagas Institute ( Portuguese ''Instituto Evandro Chagas'', or IEC) is a non-profit organization which promotes public health in Brazil named after Evandro Chagas. History In the 1940s fisherman Henrique Penna from the Rockefeller Foun ...

, but not for approval for use as a treatment for drug addiction. A phase 2a study of MM-110 treatment in patients experiencing

opioid withdrawal Opioid withdrawal is a set of symptoms arising from the sudden cessation or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs syndrome, naus ...

is set to commence in Q2 2022.

Pharmacology

18-MC is a α₃β₄

nicotinic antagonist A nicotinic antagonist is a type of anticholinergic drug that inhibits the action of acetylcholine (ACh) at nicotinic acetylcholine receptors. These compounds are mainly used for peripheral muscle paralysis in surgery, the classical agent of this t ...

and, in contrast to ibogaine, has no affinity at the α₄β₂ subtype nor at NMDA-channels nor at the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

, and has significantly reduced affinity for

sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

s and for the σ receptor, but retains modest affinity for μ-opioid receptors where it acts as an agonist, and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, 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 re ...

s. The sites of action in the brain include the

medial habenula The habenula (diminutive of Latin meaning rein) is a small bilateral neuronal structure in the brain of vertebrates, that has also been called a microstructure since it is no bigger than a pea. The naming as little rein describes its elongated ...

interpeduncular nucleus The interpeduncular nucleus (IPN) is an unpaired, ovoid group of neurons at the base of the midbrain tegmentum. In the midbrain it lies below the interpeduncular fossa. As the name suggests, the interpeduncular nucleus lies ''in between'' the cere ...

, dorsolateral

tegmentum The tegmentum (from Latin for "covering") is a general area within the brainstem. The tegmentum is the ventral part of the midbrain and the tectum is the dorsal part of the midbrain. It is located between the ventricular system and distinctive b ...

and

basolateral amygdala The basolateral amygdala, or basolateral complex, or basolateral nuclear complex consists of the lateral, basal and accessory-basal nuclei of the amygdala. The lateral nuclei receives the majority of sensory information, which arrives directly fr ...

. (±)-18-MC competitively inhibits α9α10 nAChRs with potencies higher than that at α3β4 and α4β2 nAChRs and directly blocks Ca_V2.2.

Chemistry

Derivatives

A number of derivatives of 18-MC have been developed, with several of them being superior to 18-MC itself, the methoxyethyl congener ME-18-MC being more potent than 18-MC with similar efficacy, and the methylamino analogue 18-MAC being more effective than 18-MC with around the same potency. These compounds were also found to act as selective α₃β₄ nicotinic acetylcholine antagonists, with little or no effect on NMDA receptors.

References

{{DEFAULTSORT:Methoxycoronaridine, 18- Drug rehabilitation Iboga Nicotinic antagonists NMDA receptor antagonists Kappa-opioid receptor agonists Mu-opioid receptor antagonists Opioid modulators

Pharmacology

Chemistry

Derivatives

See also

References