Long‐term antagonism and allosteric regulation of mu opioid receptors by the novel ligand, methocinnamox

Abstract

Opioid overdose is a leading cause of death in the United States. The only treatment available currently is the competitive antagonist, naloxone (Narcan®). Although naloxone is very effective and has saved many lives, as a competitive antagonist it has limitations. Due to the short half‐life of naloxone, renarcotization can occur if the ingested opioid agonist remains in the body longer. Moreover, because antagonism by naloxone is surmountable, renarcotization can also occur in the presence of naloxone if a relatively larger dose of opioid agonist is taken. In such circumstances, a long‐lasting, non‐surmountable antagonist would offer an improvement in overdose treatment. Methocinnamox (MCAM) has been reported to have a long duration of antagonist action at mu opioid receptors in vivo. In HEK cells expressing the human mu opioid receptor, MCAM antagonism of mu agonist‐inhibition of cAMP production was time‐dependent, non‐surmountable and non‐reversible, consistent with (pseudo)‐irreversible binding. In vivo, MCAM injected locally into the rat hindpaw antagonized mu agonist‐mediated inhibition of thermal allodynia for up to 96 h. By contrast, antagonism by MCAM of delta or kappa agonists in HEK cells and in vivo was consistent with simple competitive antagonism. Surprisingly, MCAM also shifted the concentration‐response curves of mu agonists in HEK cells in the absence of receptor reserve in a ligand‐dependent manner. The shift in the [D‐Ala2,N‐MePhe4,Gly‐ol5]‐enkephalin (DAMGO) concentration‐response curve by MCAM was insensitive to naloxone, suggesting that in addition to (pseudo)‐irreversible orthosteric antagonism, MCAM acts allosterically to alter the affinity and/or intrinsic efficacy of mu agonists.

Potential of Methocinnamox to Treat Opioid Misuse

“…99 As for MCAM's mechanistic interaction with DORs and KORs, the behavior was consistent in the opioid receptor expressing HEK cells, and in vivo, with simple competitive antagonism. 99 Repeated administration of MCAM every twelve days in rodents remained effective for over two-months without altering the duration of opioid withdrawal with no major ADRs and no decrease in effectiveness, suggesting positive potential for longterm OUD treatment. 19,21,96 Naltrexone, naloxone, and MCAM are effective for acute reversal and prevention of respiratory depression and other overdose symptoms due to their effects on opioid receptors, but only MCAM prevents renarcotization in the hours and days following emergency intervention.…”

“…With the intervention's limitations outlined above, MCAM may prove beneficial as a treatment to combat the opioid crisis. 106,107 , methadone 108,109 , buprenorphine 110,111 and methocinnamox (MCAM) 19,24,96,98,99,101 .…”

“…19 The evidence for pseudo-irreversible binding includes its nonreversible, insurmountable, and time-dependent antagonism of mu agonist-inhibition of cAMP production. 99 A recent study using human embryonic kidney (HEK) cells expressing human opioid receptors showed that in addition to pseudoirreversible orthosteric antagonism of MORs, directly blocking binding, MCAM also utilizes allosteric antagonism at an unknown site at a lower affinity, which alters ligand affinity and/or intrinsic efficacy of MOR agonists. 99 As for MCAM's mechanistic interaction with DORs and KORs, the behavior was consistent in the opioid receptor expressing HEK cells, and in vivo, with simple competitive antagonism.…”

“…99 A recent study using human embryonic kidney (HEK) cells expressing human opioid receptors showed that in addition to pseudoirreversible orthosteric antagonism of MORs, directly blocking binding, MCAM also utilizes allosteric antagonism at an unknown site at a lower affinity, which alters ligand affinity and/or intrinsic efficacy of MOR agonists. 99 As for MCAM's mechanistic interaction with DORs and KORs, the behavior was consistent in the opioid receptor expressing HEK cells, and in vivo, with simple competitive antagonism. 99 Repeated administration of MCAM every twelve days in rodents remained effective for over two-months without altering the duration of opioid withdrawal with no major ADRs and no decrease in effectiveness, suggesting positive potential for longterm OUD treatment.…”

“…98 MCAM binds non-competitively, making it insurmountable and therefore more effective at blocking effects of opioids in the shortand long-term. 19,24,99,100 Additionally, MCAM is naloxone-insensitive with no notable drug interactions meaning there is a possibility that the two drugs could be administered concurrently for immediate rescue and prevent subsequent renarcotization. 99 With over-the-counter availability of naloxone, overdose related deaths have decreased but subsequent renarcotization and therefore consequent overdoses leading to death remains an issue.…”