18-Methoxycoronaridine (18-MC, or MM-110) is a derivative of

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 ...

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 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 Medical Center, whi ...

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

University of Vermont The University of Vermont (UVM), officially the University of Vermont and State Agricultural College, is a public land-grant research university in Burlington, Vermont. It was founded in 1791 and is among the oldest universities in the United ...

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

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

, methamphetamine,

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. It has also been shown to produce

anorectic An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic. The term is (from the Greek ''ἀν-'' (an-) = "without" a ...

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 tenth-most populous municipality in Illinois and the fourth most populous city in Illinois outside the Chicago metro ...

, 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 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 at the Evandro Chagas Institute, 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 (a syndrome) arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, ...

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 tha ...

, 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's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the chann ...

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, 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 ...

s. The sites of action in the brain include the medial habenula,

interpeduncular nucleus The interpeduncular nucleus (IPN) is an unpaired, ovoid cell group at the base of the midbrain tegmentum. It is located in the mesencephalon below the interpeduncular fossa. As the name suggests, the interpeduncular nucleus lies ''in between'' t ...

, 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 ba ...

and basolateral amygdala. (±)-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. iboga alkaloids

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