Methoclocinnamox Explained

Methoclocinnamox (MCCAM; developmental code name NIH-10420) is a selective pseudo-irreversible partial agonist of the μ-opioid receptor (MOR).^[1] It shows a mixture of opioid agonist- and antagonist-like effects. The drug has long-lasting effects and is insurmountable by other MOR ligands.

MCCAM was derived from clocinnamox (CCAM), was first described by 1995, and was of interest in the potential treatment of opioid dependence. However, it was not further developed and was never marketed.^{[2] [3]} A close analogue of MCCAM, methocinnamox (MCAM), which in contrast to MCCAM acts as a MOR pseudo-irreversible antagonist, was first described in 2000 and is under development for the treatment of opioid use disorder and opioid overdose as of 2023.^{[4] [5]}

Pharmacology

Pharmacodynamics

MCCAM acts as a selective pseudo-irreversible partial agonist of the μ-opioid receptor (MOR). It shows both opioid agonist- and antagonist-like effects in animals. More specifically, it has analgesic effects, mixed reinforcing effects, appears to lack significant respiratory depression, alleviates opioid withdrawal symptoms, and provides long-lasting blockade and protection against the effects of MOR full agonists (including their reinforcing effects as well as their toxic and lethal effects, for instance in overdose). Due to its pseudo-irreversible nature, MCCAM is insurmountable by conventional reversible MOR ligands, for instance morphine, alfentanil, and naltrexone. MCCAM is buprenorphine-like in many regards, but differs from buprenorphine in its pseudo-irreversibility.

Pharmacokinetics

MCCAM is known to be partially metabolically converted into clocinnamox (CCAM), a MOR pseudo-irreversible antagonist. In monkeys, with oral administration of MCCAM, 70 to 80% of the drug is eliminated as conjugated CCAM, whereas with subcutaneous injection, up to 70% of the drug is excreted unchanged. As such, the metabolism of MCCAM, and by extension its effects, differ by route of administration. The metabolism of MCCAM also shows species differences between rodents and monkeys.

Chemistry

MCCAM, also known as O-methylclocinnamox, is structurally related to the MOR irreversible antagonists clocinnamox (CCAM) and methocinnamox (MCAM).^{[6] [7]} CCAM and its analogues were derived by structural modification of buprenorphine.^[8]

History

Clocinnamox (CCAM) was first described in the scientific literature by 1992.^[9] MCCAM was first described by 1995. It was developed by researchers at the National Institute on Drug Abuse (NIDA) of the United States National Institutes of Health (NIH). The drug was of interest in the possible treatment of opioid dependence. However, it was never marketed. Methocinnamox (MCAM), a close analogue of MCCAM, was first described in 2000. MCAM was under development for the treatment of opioid dependence and opioid overdose by 2020.^[10]

Notes and References

1. Book: Woods JH, Lewis JW, Winger G, Butelman E, Broadbear J, Zernig G . National Institute on Drug Abuse . Methoclocinnamox: A μ Partial Agonist With Pharmacotherapeutic Potential for Heroin Abuse . NIDA Research Monograph . National Institute on Drug Abuse . DHEW publication . v. 147 . 1995 . https://books.google.com/books?id=MtPF6qZ9l9wC&pg=PA195 . 9 August 2024 . 195–219.
2. Web site: Compound: CHEMBL386272 . EMBL-EBI . 13 September 2024.
3. Web site: D0F1EB (MC-CAM) - Therapeutic Target Database . TTD . 13 September 2024.
4. Maguire DR, France CP . Behavioral pharmacology of methocinnamox: A potential new treatment for opioid overdose and opioid use disorder . Journal of the Experimental Analysis of Behavior . 119 . 2 . 392–406 . March 2023 . 36759567 . 10281830 . 10.1002/jeab.831 .
5. Web site: Alvarez-Hernandez J . UT Health San Antonio Professor France leads novel drug discovery research . UT Health San Antonio . 7 March 2023 . 9 August 2024 . Charles P. France, PhD, the Robert A. Welch Distinguished University Chair in Chemistry, professor of pharmacology and professor of psychiatry in the Joe R. and Teresa Lozano Long School of Medicine at The University of Texas Health Science Center at San Antonio (UT Health San Antonio), recently received a $4.12 million award from the U.S. National Institutes of Health (NIH) to investigate innovative drug development research of the compound methocinnamox (MCAM) to help combat the opioid epidemic. [...] This NIH funding mechanism, specifically UG3/UH3, has one precise objective to advance the discovery into the clinical setting. "We want to get this into the clinic," France said. [...] "Under the best of conditions, we hope to have this compound into a phase one clinical trial sometime in 2024.".
6. Jordan CG, Kennalley AL, Roberts AL, Nemes KM, Dolma T, Piper BJ . The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review . Pharmacy . 10 . 3 . 48 . April 2022 . 35645327 . 9149874 . 10.3390/pharmacy10030048 . free .
7. Broadbear JH, Sumpter TL, Burke TF, Husbands SM, Lewis JW, Woods JH, Traynor JR . Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine . The Journal of Pharmacology and Experimental Therapeutics . 294 . 3 . 933–940 . September 2000 . 10945843 .
8. Book: Gerak LR, Maguire DR, France CP . Substance Use Disorders . Behavioral Pharmacology of Drugs Acting at Mu Opioid Receptors . Handbook of Experimental Pharmacology . Springer International Publishing . Cham . 258 . 2019 . 978-3-030-33678-3 . 10.1007/164_2019_265 . 127–145 . 31451969 . Given the advantages of buprenorphine as a treatment for opioid use disorder, additional compounds related to buprenorphine were synthesized in an attempt to reduce its adverse effects (Broadbear et al. 2000). These efforts resulted in the discovery of the mu opioid receptor antagonist methocinnamox (MCAM). Like buprenorphine, MCAM binds pseudoirreversibly to mu opioid receptors; however, it does not appear to produce agonist effects at mu opioid receptors under any conditions. Instead, MCAM produces long-lasting antagonism at mu opioid receptors, as evidenced by attenuation of the antinociceptive effects of morphine in rodents, with the morphine dose-effect curve shifted up to hundredfold rightward (Peckham et al. 2005) and antagonist effects evident for at least 2 days after administration (Broadbear et al. 2000)..
9. Comer SD, Burke TF, Lewis JW, Woods JH . Clocinnamox: a novel, systemically-active, irreversible opioid antagonist . The Journal of Pharmacology and Experimental Therapeutics . 262 . 3 . 1051–1056 . September 1992 . 1326622 .
10. Web site: Moss L . New drug blocks the fatal effects of opioids? . wndu.com . 4 March 2020 . 9 August 2024 . Researchers say they hope to have [methocinnamox] in human clinical trials within the next 18 to 24 months..