Methocinnamox (MCAM): A novel õ-opioid receptor antagonist for opioid use disorders

摘要/摘要 本申请为家长津贴UG3DA048387，是为回应特别利益通知 NOT-DA-21-032“芬太尼及其衍生物研究的行政补充资料”。阿片类药物危机 在新冠肺炎大流行期间显著恶化，部分原因是芬太尼的可用性增加 以及有效的芬太尼类似物。许多过量涉及一种以上的药物，通常是阿片类药物和兴奋剂药物， 尽管尚不清楚兴奋剂是否会改变阿片类药物的毒性效应，并通过以下方式逆转这些效应 纳洛酮。纳洛酮的价值受到其作用时间短的限制，其拮抗作用可能是 通过服用更多的激动剂来克服。在从过量服药中抢救出来后，纳洛酮的保护作用通常在 阿片受体激动剂作用减弱，可能导致呼吸性抑郁复发 导致死亡。如果患者持续服用纳洛酮，可能会发生致命的呼吸性抑郁。 服用阿片类药物，有报告称需要更大剂量和/或更频繁地给药 纳洛酮逆转和预防芬太尼过量与其他药物逆转过量的比较 阿片类药物。美托卡莫司(MCAM)是一种长效的阿片受体拮抗剂，可以逆转和预防 芬太尼的呼吸机抑制作用。目前尚不清楚MCAM是否在 不同阿片类药物逆转呼吸性抑郁。一些研究表明阿片受体拮抗剂，如 与纳洛酮和纳曲酮一样，不能同等地阻断不同阿片类药物和拮抗剂混合物的作用 可能比单独使用拮抗剂更有效。本提案中的研究将涉及以下内容：1)调查 海洛因和芬太尼及其类似物对呼吸性抑制的逆转和保护作用；2)比较 新型阿片受体拮抗剂MCAM与纳洛酮和MCAM/纳洛酮混合物；3)表征 海洛因/甲基苯丙胺和芬太尼/甲基苯丙胺混合液的呼吸机抑制效应 纳洛酮和MCAM单独和一起逆转这些影响；以及4)测试 阿片类药物的呼吸机抑制作用及纳洛酮和MCAM的逆转作用 在一起。两个特定的目标将检验以下假设：1)纳洛酮逆转呼吸的效力较弱 芬太尼及其类似物与海洛因逆转呼吸性抑郁的比较 MCAM在逆转所有四种阿片类药物的呼吸性抑制方面具有相似的效力；3)甲基苯丙胺 不改变芬太尼或海洛因的呼吸抑制作用，也不能被拮抗剂逆转； 4)MCAM和纳洛酮的混合使用比单独使用任何一种拮抗剂都更有效地逆转和保护 抗呼吸性抑郁；5)在本研究中，药物的效果没有性别差异。通过 不同阿片类药物单独和与甲基苯丙胺一起逆转呼吸性抑制的特征，这些 研究将有助于指导过量的治疗，可能包括新的阿片受体拮抗剂，如 MCAM或拮抗剂的混合物。

ABSTRACT/SUMMARY This application for a supplement to parent grant UG3DA048387 is in response to Notice of Special Interest NOT-DA-21-032 “Administrative Supplements for research on fentanyl and derivatives.” The opioid crisis has worsened significantly during the COVID-19 pandemic, in part because of increasing availability of fentanyl and potent fentanyl analogs. Many overdoses involve more than one drug, often an opioid and a stimulant drug, although it is unclear whether stimulants alter the toxic effects of opioids and reversal of those effects by naloxone. The value of naloxone is limited by its short duration of action and that its antagonism can be surmounted by taking more agonist. After rescue from overdose, protection by naloxone often wanes before the effects of the opioid receptor agonist decrease, resulting in the reemergence of ventilatory depression possibly leading to death. Fatal ventilatory depression can occur in the presence of naloxone if an individual continues taking opioids, and there are reports of the need for larger doses and/or more frequent administration of naloxone to reverse and protect against overdose from fentanyl, compared with reversal of overdose from other opioids. Methocinnamox (MCAM) is a long-acting µ opioid receptor antagonist that reverses and prevents the ventilatory-depressant effects of fentanyl. It is not known whether MCAM is equally effective (potent) in reversing ventilatory depression by different opioids. Some studies suggest that opioid receptor antagonists, such as naloxone and naltrexone, do not block effects of different opioids equally and that mixtures of antagonists might be more effective than antagonists alone. Studies in this proposal will address the following: 1) investigate reversal of and protection from ventilatory depression by heroin and by fentanyl and related analogs; 2) compare the novel opioid receptor antagonist MCAM with naloxone and MCAM/naloxone mixtures; 3) characterize the ventilatory-depressant effects of heroin/methamphetamine and fentanyl/methamphetamine mixtures and reversal of those effects by naloxone and MCAM, alone and together; and 4) test for sex differences in the ventilatory-depressant effects of opioids and reversal of those effects by naloxone and MCAM, alone and together. Two specific aims will test the following hypotheses: 1) naloxone is less potent at reversing ventilatory depression by fentanyl and related analogs compared with reversal of ventilatory depression by heroin; 2) MCAM has similar potency at reversing ventilatory depression by all four opioids; 3) methamphetamine does not alter the ventilatory-depressant effects of fentanyl or heroin nor reversal of those effects by antagonists; 4) mixtures of MCAM and naloxone are more effective than either antagonist alone at reversing and protecting against ventilatory depression; and 5) there are no sex differences in the effects of drugs in this study. By characterizing reversal of ventilatory depression of different opioids alone and with methamphetamine, these studies will help guide the treatment of overdose, perhaps including novel opioid receptor antagonists like MCAM or mixtures of antagonists.