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

摘要/总结 本申请是对特别兴趣通知的回应，以补充父母补助金UG 3DA 048387 NOT-DA-21-032“芬太尼及其衍生物研究的行政补充”。阿片类药物危机 在COVID-19大流行期间显著恶化，部分原因是芬太尼的可用性增加 和强效芬太尼类似物。许多药物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改变阿片类药物的毒性作用， 纳洛酮纳洛酮的价值受到其作用持续时间短的限制，并且其拮抗作用可能是 服用更多的激动剂。从过量抢救后，纳洛酮的保护作用往往在药物过量之前减弱。 阿片受体激动剂的作用降低，可能导致抑郁症的复发。 导致死亡如果一个人继续服用纳洛酮， 服用阿片类药物，有报告称需要更大剂量和/或更频繁地给予阿片类药物， 纳洛酮逆转和防止芬太尼过量，与逆转其他药物过量相比 阿片类药物Methocinnamox（MCAM）是一种长效μ阿片受体拮抗剂，可逆转和预防 芬太尼的呼吸抑制作用。目前尚不清楚MCAM是否同样有效（有效）， 通过不同的阿片类药物逆转抑郁症。一些研究表明，阿片受体拮抗剂，如 如纳洛酮和纳洛酮，不能同等地阻断不同阿片类药物的作用， 可能比单独的拮抗剂更有效。本提案中的研究将解决以下问题：1）调查 海洛因和芬太尼及相关类似物对抑郁症的逆转和保护作用; 2）比较 新的阿片受体拮抗剂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/甲基苯丙胺混合物的通气抑制作用， 纳洛酮和MCAM单独和一起逆转这些作用;和4）测试在 阿片类药物的通气抑制作用以及纳洛酮和MCAM单独和 一起两个具体的目标将测试以下假设：1）纳洛酮在逆转急性毒性方面的效力较低， 芬太尼和相关类似物与海洛因逆转抑郁症的比较; 2） MCAM在逆转所有四种阿片类药物引起的抑郁症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通气抑制作用，也不通过拮抗剂逆转这些作用; 4)MCAM和纳洛酮的混合物在逆转和保护 5）在本研究中药物的作用没有性别差异。通过 特征逆转不同的阿片类药物单独和甲基苯丙胺，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， 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.