Methocinnamox
Opioid antagonist
From Wikipedia, the free encyclopedia
Methocinnamox (MCAM) is an opioid receptor antagonist.[1][2] It is a pseudo-irreversible non-competitive antagonist of the μ-opioid receptor and a competitive antagonist of the κ- and δ-opioid receptors.[1][2] The drug has a very long duration of action of up to months with a single dose due to its pseudo-irreversibility.[1][2] It is administered in animals by intravenous or subcutaneous injection.[1]
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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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| Chemical and physical data | |
| Formula | C30H32N2O4 |
| Molar mass | 484.596 g·mol−1 |
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It was first described in the scientific 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 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.[1][2] Clinical trials of the drug are expected.[3][5]
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).[6][7] The drug was derived via structural modification of buprenorphine.[8]
Pharmacology
Pharmacodynamics
Methocinnamox is an opioid receptor antagonist, it works at the μ-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 as heroin and fentanyl.[1][2] It is a pseudo-irreversible non-competitive antagonist of the μ-opioid receptor and a competitive antagonist of the κ- and δ-opioid receptors.[1][2]
Methocinnamox has affinity values for the opioid 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 a covalent bond with the receptor.[2] This is in contrast to prototypical μ-opioid receptor alkylating agents like β-funaltrexamine and β-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 more selective 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 the orthosteric 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 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.[1]
The μ-opioid receptor antagonism of methocinnamox is non-competitive and insurmountable by μ-opioid receptor agonists like morphine 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 the dose–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 like naloxone and naltrexone, 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 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.[2]
The actions of methocinnamox are dose-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]
Pharmacokinetics
In animals, methocinnamox reached peak concentrations 15 to 45 minutes following injection and had an elimination 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 to pharmacokinetic factors but rather its pharmacodynamic properties and pseudo-irreversible antagonism.[1]
Chemistry
In terms of chemical structure, methocinnamox is a cinnamoylamidomorphinan and is closely related to clocinnamox and methoclocinnamox.[2][6] It was derived via structural modification of buprenorphine.[8]
History
Clocinnamox was first described in the scientific literature by 1992.[10] Methoclocinnamox, which is metabolically converted into clocinnamox and is a μ-opioid receptor partial agonist, was first described by 1995.[11] Methocinnamox was first described in 2000.[1][3][4]
Research
Opioid overdose and/or opioid use disorder
Methocinnamox is able to reverse the respiratory depressant effects of fentanyl and heroin in animals.[1][12][13][14] However, unlike naloxone, another opioid antagonist, its action lasts around 2 weeks if administered subcutaneously and up to 5 days if administered intravenously.[1][15] This could make it a better antidote than naloxone in opioid 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 that clinical trials of methocinnamox were expected to begin within 18 to 24 months.[3] 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.[5]