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| Clinical data | |
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| Other names | MCAM; M-CAM |
| Routes of administration | Intravenous,subcutaneous injection[1] |
| Drug class | Opioid receptor antagonist[1] |
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| CAS Number | |
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| ChEMBL | |
| Chemical and physical data | |
| Formula | C30H32N2O4 |
| Molar mass | 484.596 g·mol−1 |
| 3D model (JSmol) | |
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Methocinnamox (MCAM) is anopioid receptor antagonist.[1][2] It is apseudo-irreversiblenon-competitiveantagonist of theμ-opioid receptor and acompetitive antagonist of theκ- andδ-opioid receptors.[1][2] The drug has a very longduration of action of up to months with a single dose due to its pseudo-irreversibility.[1][2] It is administered in animals byintravenous orsubcutaneous injection.[1]
It was first described in thescientific literature in 2000.[1][3][4] It has not been studied in humans as of 2022.[1] There is interest in methocinnamox in the potential treatment ofopioid use disorder andopioid overdose due to its much longer-lasting and insurmountable effects relative to other opioid antagonists likenaloxone andnaltrexone.[1][2]Clinical trials of the drug are expected.[3][5]
Methocinnamox should not be confused withmethoclocinnamox (MCCAM), which is aclosely related but structurally differentcompound (chlorine instead ofmethyl on one of thebenzenerings).[6][7] The drug wasderived viastructural modification ofbuprenorphine.[8]
Methocinnamox is anopioid receptor antagonist, it works at theμ-opioid receptor.[1][2][9] By acting as an antagonist, it binds to the receptor but does not activate it, thus blocking the action of agonists such asheroin andfentanyl.[1][2] It is apseudo-irreversiblenon-competitiveantagonist of the μ-opioid receptor and acompetitive antagonist of theκ- andδ-opioid receptors.[1][2]
Methocinnamox hasaffinity values for theopioid receptors of 0.6 nM for the μ-opioid receptor, 2.2 nM for the δ-opioid receptor, and 4.9 nM for the κ-opioid receptor.[2] 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.[2]
The antagonism of the μ-opioid receptor by methocinnamox is not irreversible as the drug does not form acovalent bond with the receptor.[2] This is in contrast to prototypical μ-opioid receptoralkylating agents likeβ-funaltrexamine andβ-chlornaltrexamine.[2][4] 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.[2] Hence, methocinnamox has been described as a pseudo-irreversible antagonist of the μ-opioid receptor or as a "functionally irreversible" antagonist.[2] The mechanism underlying the pseudo-irreversible antagonism of methocinnamox hasn't been fully elucidated.[1] Also unlike irreversible μ-opioid receptor antagonists like β-funaltrexamine and β-chlornaltrexamine, methocinnamox lacks κ-opioid receptor agonism and is moreselective for the μ-opioid receptor in its actions.[4]
Methocinnamox has been found to bind to two distinct sites on the μ-opioid receptor.[1] It binds to theorthosteric site as a pseudo-irreversible and non-competitive antagonist, thereby directly blocking opioid binding.[1] In addition, methocinnamox has been found to bind to and act as an antagonist of an unknownallosteric site on the μ-opioid receptor with lower affinity that modulates the affinity and/orintrinsic activity of orthosteric μ-opioid receptor agonists.[1]
The μ-opioid receptor antagonism of methocinnamox is non-competitive and insurmountable by μ-opioid receptor agonists likemorphine and fentanyl.[2][1] It has been found to completely block the effects of morphine at morphine doses of up to 1,000 mg/kg in animals, with thedose–response curve of morphine being shifted rightward by up to 100-fold.[2][8] Doses of morphine of 1,000 mg/kg are normally often fatal.[2] The insurmountability of methocinnamox's μ-opioid receptor antagonism is in contrast to that with competitive μ-opioid receptor antagonists likenaloxone andnaltrexone, which can be overcome with higher doses of μ-opioid receptor agonists.[1][2]
In contrast to the μ-opioid receptor, the antagonism of the κ- and δ-opioid receptors by methocinnamox is competitive and reversible.[1] Moreover, methocinnamox shows a short duration in the body.[1] The actions of methocinnamoxin vivo are selective for μ-opioid receptor antagonism, with a lack of significant antagonism of the effects of κ-opioid receptor agonists likebremazocine or δ-opioid receptor agonists likeBW373U86.[2]
The actions of methocinnamox aredose-dependent.[2] A single dose of 3.2 mg/kg blocked the effects of morphine for approximately 2 weeks in animals whereas a single 10 mg/kg dose blocked the effects of morphine for over 2 months.[2]
In animals, methocinnamox reachedpeak concentrations 15 to 45 minutes followinginjection and had anelimination half-life of approximately 70 minutes.[1] 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.[1][2] These findings suggest that the long-lasting effects of methocinnamox are not due topharmacokinetic factors but rather itspharmacodynamic properties and pseudo-irreversible antagonism.[1]
In terms ofchemical structure, methocinnamox is acinnamoylamidomorphinan and is closely related toclocinnamox andmethoclocinnamox.[2][6] It wasderived viastructural modification ofbuprenorphine.[8]
Clocinnamox was first described in thescientific literature by 1992.[10]Methoclocinnamox, which ismetabolically converted into clocinnamox and is aμ-opioid receptorpartial agonist, was first described by 1995.[11] Methocinnamox was first described in 2000.[1][3][4]
Methocinnamox is able to reverse therespiratory depressant effects offentanyl andheroin in animals.[1][12][13][14] However, unlikenaloxone, anotheropioid antagonist, its action lasts around 2 weeks if administeredsubcutaneously and up to 5 days if administeredintravenously.[1][15] This could make it a betterantidote than naloxone inopioid overdoses, because naloxone usually lasts around 30 minutes, there is a need for repeated administration and a danger of renarcotization.[1][16] By acting longer, methocinnamox prevents these dangers.[1]
Methocinnamox has not yet been tested in humans as of 2022.[1] However, it has been tested in rodents and monkeys.[2] It was reported in March 2020 thatclinical trials of methocinnamox were expected to begin within 18 to 24 months.[3] In March 2023, it was reported that aphase 1 clinical trial of methocinnamox funded by theNational Institutes of Health (NIH) would possibly start in 2024.[5]
Researchers say they hope to have [methocinnamox] in human clinical trials within the next 18 to 24 months.
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."
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).
