Methocinnamox
{{Short description|Opioid antagonist}}
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{{Distinguish|Methoclocinnamox}}
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| routes_of_administration = Intravenous, subcutaneous injection
| class = Opioid receptor antagonist
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| CAS_number = 117339-76-1
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| PubChem = 46877713
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| ChemSpiderID = 24673142
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| ChEMBL = 610884
| synonyms = MCAM; M-CAM
| C=30 | H=32 | N=2 | O=4
| IUPAC_name = (E)-N-[(4R,4aS,7aR,12bR)-3-(Cyclopropylmethyl)-9-hydroxy-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-yl]-3-(4-methylphenyl)prop-2-enamide
| SMILES = CC1=CC=C(C=C1)/C=C/C(=O)N[C@@]23CCC(=O)[C@H]4[C@@]25CCN([C@@H]3CC6=C5C(=C(C=C6)O)O4)CC7CC7
| StdInChI_Ref =
| StdInChI = 1S/C30H32N2O4/c1-18-2-4-19(5-3-18)8-11-25(35)31-30-13-12-23(34)28-29(30)14-15-32(17-20-6-7-20)24(30)16-21-9-10-22(33)27(36-28)26(21)29/h2-5,8-11,20,24,28,33H,6-7,12-17H2,1H3,(H,31,35)/b11-8+/t24-,28+,29+,30-/m1/s1
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| StdInChIKey = PJOHVEQSYPOERL-SHEAVXILSA-N
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Methocinnamox (MCAM) is an opioid receptor antagonist.{{cite journal | vauthors = Jordan CG, Kennalley AL, Roberts AL, Nemes KM, Dolma T, Piper BJ | title = The Potential of Methocinnamox as a Future Treatment for Opioid Use Disorder: A Narrative Review | journal = Pharmacy | volume = 10 | issue = 3 | page = 48 | date = April 2022 | pmid = 35645327 | pmc = 9149874 | doi = 10.3390/pharmacy10030048 | doi-access = free }} It is a pseudo-irreversible non-competitive antagonist of the μ-opioid receptor and a competitive antagonist of the κ- and δ-opioid receptors. The drug has a very long duration of action of up to months with a single dose due to its pseudo-irreversibility. It is administered in animals by intravenous or subcutaneous injection.
It was first described in the scientific literature in 2000.{{cite journal | vauthors = Broadbear JH, Sumpter TL, Burke TF, Husbands SM, Lewis JW, Woods JH, Traynor JR | title = Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 294 | issue = 3 | pages = 933–940 | date = September 2000 | pmid = 10945843 | doi = | url = https://jpet.aspetjournals.org/content/294/3/933.long }} It has not been studied in humans as of 2022. There is interest in methocinnamox in the potential treatment of opioid use disorder and opioid overdose due to its much longer-lasting and insurmountable effects relative to other opioid antagonists like naloxone and naltrexone.{{cite journal | vauthors = Maguire DR, France CP | title = Behavioral pharmacology of methocinnamox: A potential new treatment for opioid overdose and opioid use disorder | journal = Journal of the Experimental Analysis of Behavior | volume = 119 | issue = 2 | pages = 392–406 | date = March 2023 | pmid = 36759567 | pmc = 10281830 | doi = 10.1002/jeab.831 }} Clinical trials of the drug are expected.{{cite web | last=Alvarez-Hernandez | first=Jane | title=UT Health San Antonio Professor France leads novel drug discovery research | website=UT Health San Antonio | date=7 March 2023 | url=https://news.uthscsa.edu/ut-health-san-antonio-professor-france-leads-novel-drug-discovery-research/ | access-date=9 August 2024 | quote=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."}}
Methocinnamox should not be confused with methoclocinnamox (MCCAM), which is a closely related but structurally different compound (chlorine instead of methyl on one of the benzene rings).{{cite thesis | vauthors = Neilan CL | title=In vitro and in vivo characterisation of buprenorphine and other long-lasting opioids | publisher=Loughborough University | date=8 August 2019 | url=https://repository.lboro.ac.uk/articles/thesis/In_vitro_and_in_vivo_characterisation_of_buprenorphine_and_other_long-lasting_opioids/9398774?file=17014466 | access-date=9 August 2024}}{{cite web | title=Methoclocinnamox | work = PubChem | publisher = U.S. National Library of Medicine | url=https://pubchem.ncbi.nlm.nih.gov/compound/6438373 | access-date=9 August 2024}} The drug was derived via structural modification of buprenorphine.{{cite book | vauthors = Gerak LR, Maguire DR, France CP | title=Substance Use Disorders | chapter=Behavioral Pharmacology of Drugs Acting at Mu Opioid Receptors | series=Handbook of Experimental Pharmacology | publisher=Springer International Publishing | publication-place=Cham | volume=258 | date=2019 | isbn=978-3-030-33678-3 | doi=10.1007/164_2019_265 | pages=127–145 | pmid=31451969 | quote=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).}}
Pharmacology
=Pharmacodynamics=
Methocinnamox is an opioid receptor antagonist, it works at the μ-opioid receptor.{{cite journal | vauthors = Gerak LR, Minervini V, Latham E, Ghodrati S, Lillis KV, Wooden J, Disney A, Husbands SM, France CP | title = Methocinnamox Produces Long-Lasting Antagonism of the Behavioral Effects of µ-Opioid Receptor Agonists but Not Prolonged Precipitated Withdrawal in Rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 371 | issue = 2 | pages = 507–516 | date = November 2019 | pmid = 31439807 | pmc = 6863459 | doi = 10.1124/jpet.119.260331 }} By acting as an antagonist, it binds to the receptor but does not activate it, thus blocking the action of agonists such as heroin and fentanyl. It is a pseudo-irreversible non-competitive antagonist of the μ-opioid receptor and a competitive antagonist of the κ- and δ-opioid receptors.
Methocinnamox has affinity values for the opioid receptors of 0.6{{nbsp}}nM for the μ-opioid receptor, 2.2{{nbsp}}nM for the δ-opioid receptor, and 4.9{{nbsp}}nM for the κ-opioid receptor. Hence, it has about 3.7-fold preferential affinity for the μ-opioid receptor over the δ-opioid receptor and about 8.2-fold higher affinity for the μ-opioid receptor over the κ-opioid receptor.
The antagonism of the μ-opioid receptor by methocinnamox is not irreversible as the drug does not form a covalent bond with the receptor. This is in contrast to prototypical μ-opioid receptor alkylating agents like β-funaltrexamine and β-chlornaltrexamine. However, in spite of its lack of covalent binding to the μ-opioid receptor, methocinnamox appears to not dissociate from the μ-opioid receptor or dissociates from it extremely slowly. Hence, methocinnamox has been described as a pseudo-irreversible antagonist of the μ-opioid receptor or as a "functionally irreversible" antagonist. The mechanism underlying the pseudo-irreversible antagonism of methocinnamox hasn't been fully elucidated. Also unlike irreversible μ-opioid receptor antagonists like β-funaltrexamine and β-chlornaltrexamine, methocinnamox lacks κ-opioid receptor agonism and is more selective for the μ-opioid receptor in its actions.
Methocinnamox has been found to bind to two distinct sites on the μ-opioid receptor. It binds to the orthosteric site as a pseudo-irreversible and non-competitive antagonist, thereby directly blocking opioid binding. In addition, methocinnamox has been found to bind to and act as an antagonist of an unknown allosteric site on the μ-opioid receptor with lower affinity that modulates the affinity and/or intrinsic activity of orthosteric μ-opioid receptor agonists.
The μ-opioid receptor antagonism of methocinnamox is non-competitive and insurmountable by μ-opioid receptor agonists like morphine and fentanyl. It has been found to completely block the effects of morphine at morphine doses of up to 1,000{{nbsp}}mg/kg in animals, with the dose–response curve of morphine being shifted rightward by up to 100-fold. Doses of morphine of 1,000{{nbsp}}mg/kg are normally often fatal. The insurmountability of methocinnamox's μ-opioid receptor antagonism is in contrast to that with competitive μ-opioid receptor antagonists like naloxone and naltrexone, which can be overcome with higher doses of μ-opioid receptor agonists.
In contrast to the μ-opioid receptor, the antagonism of the κ- and δ-opioid receptors by methocinnamox is competitive and reversible. Moreover, methocinnamox shows a short duration in the body. The actions of methocinnamox in vivo are selective for μ-opioid receptor antagonism, with a lack of significant antagonism of the effects of κ-opioid receptor agonists like bremazocine or δ-opioid receptor agonists like BW373U86.
The actions of methocinnamox are dose-dependent. A single dose of 3.2{{nbsp}}mg/kg blocked the effects of morphine for approximately 2{{nbsp}}weeks in animals whereas a single 10{{nbsp}}mg/kg dose blocked the effects of morphine for over 2{{nbsp}}months.
=Pharmacokinetics=
In animals, methocinnamox reached peak concentrations 15 to 45{{nbsp}}minutes following injection and had an elimination half-life of approximately 70{{nbsp}}minutes. In spite of this short duration in the body however, the μ-opioid receptor antagonist effects of methocinnamox persist for up to months with a single injection. These findings suggest that the long-lasting effects of methocinnamox are not due to pharmacokinetic factors but rather its pharmacodynamic properties and pseudo-irreversible antagonism.
Chemistry
In terms of chemical structure, methocinnamox is a cinnamoylamidomorphinan and is closely related to clocinnamox and methoclocinnamox. It was derived via structural modification of buprenorphine.
History
Clocinnamox was first described in the scientific literature by 1992.{{cite journal | vauthors = Comer SD, Burke TF, Lewis JW, Woods JH | title = Clocinnamox: a novel, systemically-active, irreversible opioid antagonist | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 262 | issue = 3 | pages = 1051–1056 | date = September 1992 | pmid = 1326622 | doi = }} Methoclocinnamox, which is metabolically converted into clocinnamox and is a μ-opioid receptor partial agonist, was first described by 1995.{{cite book | vauthors = Woods JH, Lewis JW, Winger G, Butelman E, Broadbear J, Zernig G | editor=National Institute on Drug Abuse | chapter = Methoclocinnamox: A μ Partial Agonist With Pharmacotherapeutic Potential for Heroin Abuse | title=NIDA Research Monograph | publisher=National Institute on Drug Abuse | series=DHEW publication | issue=v. 147 | year=1995 | chapter-url=https://books.google.com/books?id=MtPF6qZ9l9wC&pg=PA195 | access-date=9 August 2024 | pages=195–219}} Methocinnamox was first described in 2000.
Research
=Opioid overdose and/or opioid use disorder=
Methocinnamox is able to reverse the respiratory depressant effects of fentanyl and heroin in animals.{{cite journal | vauthors = Gerak LR, Maguire DR, Woods JH, Husbands SM, Disney A, France CP | title = Reversal and Prevention of the Respiratory-Depressant Effects of Heroin by the Novel μ-Opioid Receptor Antagonist Methocinnamox in Rhesus Monkeys | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 368 | issue = 2 | pages = 229–236 | date = February 2019 | pmid = 30463875 | pmc = 6337004 | doi = 10.1124/jpet.118.253286 }}{{cite conference | vauthors = Hiranita T, Ho NP, France CP | title=ASPET 2023 Annual Meeting Abstract - Central Nervous System Pharmacology - Neuropharmacology | chapter=Comparison of the mu-opioid receptor antagonists methocinnamox (MCAM) and naloxone to reverse the ventilatory-depressant effects of fentanyl and heroin in male rats | publisher=American Society for Pharmacology and Experimental Therapeutics | date=2023 | doi=10.1124/jpet.122.155410 | page=544}}{{cite journal | vauthors = Jimenez VM, Castaneda G, France CP | title = Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 377 | issue = 1 | pages = 29–38 | date = April 2021 | pmid = 33431611 | pmc = 7985616 | doi = 10.1124/jpet.120.000387 }} However, unlike naloxone, another opioid antagonist, its action lasts around 2{{nbsp}}weeks if administered subcutaneously and up to 5{{nbsp}}days if administered intravenously.{{cite journal | vauthors = Jimenez VM, Castaneda G, France CP | title = Methocinnamox Reverses and Prevents Fentanyl-Induced Ventilatory Depression in Rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 377 | issue = 1 | pages = 29–38 | date = April 2021 | pmid = 33431611 | pmc = 7985616 | doi = 10.1124/jpet.120.000387 }} This could make it a better antidote than naloxone in opioid overdoses, because naloxone usually lasts around 30{{nbsp}}minutes, there is a need for repeated administration and a danger of renarcotization.{{Cite web |title=Opioid Overdose Limitations in Naloxone Reversal |url=https://pubs.asahq.org/anesthesiology/article/139/3/342/138415/Opioid-Overdose-Limitations-in-Naloxone-Reversal |access-date=2024-02-11 |website=pubs.asahq.org}} By acting longer, methocinnamox prevents these dangers.
Methocinnamox has not yet been tested in humans as of 2022. However, it has been tested in rodents and monkeys. It was reported in March 2020 that clinical trials of methocinnamox were expected to begin within 18 to 24{{nbsp}}months.{{cite web | vauthors = Moss L | title=New drug blocks the fatal effects of opioids? | website=wndu.com | date=4 March 2020 | url=https://www.wndu.com/content/news/New-drug-blocks-the-fatal-effects-of-opioids-568493251.html | access-date=9 August 2024 | quote = Researchers say they hope to have [methocinnamox] in human clinical trials within the next 18 to 24 months.}} In March 2023, it was reported that a phase 1 clinical trial of methocinnamox funded by the National Institutes of Health (NIH) would possibly start in 2024.