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

Methocinnamox (MCAM)：一种新型 α-阿片受体拮抗剂，用于治疗阿片类药物使用障碍

• 批准号: 10477526
• 负责人: CHARLES P FRANCE
• 金额: $ 14.8万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477526
• 关键词: Address; Administrative Supplement; Agonist; COVID-19 pandemic; Cessation of life; Clinical; Clinical Trials; Dose; FDA approved; Female; Fentanyl; Grant; Heroin; Individual; Laboratories; Literature; Methamphetamine; Methocinnamox; Morphinans; Naloxone; Naltrexone; Opioid; Opioid Antagonist; Opioid agonist; Overdose; Overdose reversal; Parents; Pharmaceutical Preparations; Rattus; Reporting; Research; Sex Differences; Stimulant; Testing; Toxic effect; U-Series Cooperative Agreements; United States National Institutes of Health; Ventilatory Depression; analog; antagonist; carfentanil; experimental study; fentanyl overdose; interest; lipophilicity; male; mu opioid receptors; novel; opioid epidemic; opioid overdose; opioid use disorder; overdose death; parent grant; prevent; response

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.

摘要/摘要 此申请补充父母赠款UG3DA048387是为了回应特殊利益的通知 NOT-DA-21-032“用于芬太尼和衍生物的研究的行政补品”。阿片类药物危机 不幸的是，在Covid-19-19大流行期间显着，部分原因是芬太尼的可用性增加 和有效的芬太尼类似物。许多过量服用涉及多种药物，通常是阿片类药物和一种兴奋剂， 尽管尚不清楚兴奋剂是否改变了阿片类药物的毒性作用和这些影响的逆转 纳洛酮。纳洛酮的价值受其作用持续时间短的限制，其对抗可以是 通过吸引更多的激动剂来克服。从服药过量中营救后，纳洛酮的保护经常在 阿片类药物受体激动剂下降的影响，导致通风抑郁的重新出现 导致死亡。如果一个人继续 服用阿片类药物，有报道说需要更大剂量和/或更频繁地给药 纳洛酮逆转并预防过量服用过量，与其他过量相反 OOPIOIDS。甲氧蛋白（MCAM）是一种长效µ o o o o o中受体拮抗剂，可逆转并防止 芬太尼的通气抑制作用。尚不知道MCAM是否同样有效（有效） 不同阿片类药物逆转通风抑郁症。一些研究表明阿片受体拮抗剂，这样 作为纳洛酮和纳曲酮，请勿平等地阻断不同阿片类药物的作用，并且会混合拮抗剂 可能比单独对手更有效。该提案中的研究将解决以下内容：1）调查 海洛因和芬太尼和相关类似物的逆转和防止通风抑郁症； 2）比较 新型的阿片受体拮抗剂MCAM MCAM，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以及 纳洛酮和MCAM逆转了这些影响，单独和共同逆转； 4）测试性别差异 阿片类药物的通气抑制作用以及纳洛酮和MCAM的逆转，单独使用， 一起。两个具体目标将检验以下假设：1）纳洛酮在逆转通风方面的潜力较小 与海洛因的通风抑郁症相比，芬太尼和相关类似物的抑郁症； 2） MCAM在所有四种阿片类药物的逆转通风抑郁方面具有类似的效力。 3）甲基苯丙胺可以 不会改变芬太尼或海洛因的通气抑制作用，也不会改变拮抗剂对这些作用的逆转； 4）MCAM和NALOXONE的混合物比单独逆转和保护的任何拮抗剂更有效 反对通风抑郁症； 5）在这项研究中，药物的影响没有性别差异。经过 表征单独和甲基苯丙胺的不同阿片类药物的通风抑郁症的逆转，这些 研究将有助于指导过量的治疗，也许包括新型阿片类药物拮抗剂 MCAM或拮抗剂的混合物。