ARTT Center of Excellence
ARTT Inaugural Pilot Project Update:
MCAM: A long-acting antagonist for treatment of opioid overdose
The most effective treatment for opioid overdose is administration of an opioid receptor antagonist which can quickly reverse the potentially lethal respiratory depression produced by large doses of opioid agonists. Currently, the only opioid antagonist available to first-responders to reverse opioid overdose is naloxone, a compound that is short-acting and can be overcome (i.e., surmounted) by potent, long-acting opioid agonists. Our preliminary data suggest that the novel opioid receptor antagonist, methocinnamox (MCAM), has a long duration of action and we hypothesize that this is due to irreversible opioid receptor binding properties (e.g., non-surmountability). In an overdose situation, the advantage of a long-acting antagonist like MCAM over a short acting antagonist such as naloxone is that a single administration would suffice to protect an individual against a return of respiratory depression, even if he or she has taken a very long acting opioid agonist. Because MCAM has received only cursory evaluation to date, our pilot project sponsored by the ARTT Center is focused on rigorous characterization of MCAM in comparison to that of naloxone both in vitro and in vivo.
Our in vitro experiments are designed to characterize the antagonist properties of MCAM in comparison to that of naloxone for opioid receptor-mediated signaling in HEK293 cells. Results from these experiments will provide the nature of the antagonist effects (simple, competitive antagonism vs non- competitie antagonism and irreversibility) as well as the duration of antagonism of MCAM versus that of naloxone. In vivo, we are evaluating the antagonist properties of MCAM using whole body plethysmograph recordings in rats. The ability of MCAM to prevent respiratory depression produced by abused opioids (e.g., fentanyl, heroin) as well as the duration of antagonism are being determined.
If our hypothesis that MCAM is an irreversible antagonist at mu opioid receptors is true, we expect that MCAM will be vastly superior to naloxone for treatment of opioid overdose and perhaps useful to prevent opioid abuse.
James H Woods, Gail D Winger, William P Clarke and Kelly A Berg