Pharmacological and behavioral effects of MCAM: a long-acting, μ opioid receptor antagonist for treatment of opioid overdose and opioid abuse disorder

MCAM 的药理和行为影响：一种长效、μ阿片受体拮抗剂，用于治疗阿片类药物过量和阿片类药物滥用障碍

• 批准号: 10091419
• 负责人: WILLIAM P CLARKE
• 金额: $ 46.18万
• 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: 2019-05-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091419
• 关键词: Absence of pain sensation; Agonist; Analgesics; Behavioral; Binding; Body Weight decreased; Canis familiaris; Catheters; Characteristics; Chronic; Coupled; Data; Dependence; Diarrhea; Disease; Dissociation; Dose; Effectiveness; Epidemic; Fentanyl; Formulation; Human; Implant; In Vitro; Individual; Intravenous; Kinetics; Lead; Local Anesthetics; Measures; Methocinnamox; Modeling; Morphine; Naloxone; Naltrexone; Neurons; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid Receptor; Opioid agonist; Organism; Overdose; Pain; Pain management; Peripheral; Pharmaceutical Preparations; Pharmacology; Preparation; Property; Rattus; Recrudescences; Regulation; Self Administration; Signal Pathway; Signal Transduction; System; Testing; Time; Toxic effect; United States; Ventilatory Depression; Whole Body Plethysmography; Withdrawal; Work; improved; in vivo; kappa opioid receptors; mu opioid receptors; mu receptors; novel; opioid abuse; opioid overdose; opioid withdrawal; peripheral pain; prevent; receptor; receptor function; remifentanil

Methocinnamox (MCAM) is a long-acting µ-opioid receptor antagonist that may have distinct advantages in the treatment of both opioid overdose and opioid abuse disorder. We propose to evaluate MCAM using in vitro and in vivo measures, comparing the actions of MCAM with those of the opioid antagonists naltrexone and naloxone, that are currently used to treat abuse and overdose, respectively. We hypothesize that differences in pharmacological properties, including binding kinetics and non-surmountablility by opioids of abuse, will distinguish MCAM from those of the other opioid receptor antagonists. In vitro, we will compare MCAM to naloxone for kinetics of association/dissociation, surmountability by opioid agonists (fentanyl, morphine), the duration of antagonism (is MCAM irreversible?), and determine the pharmacological characteristics of MCAM at multiple cellular signaling pathways. In vivo measures will be taken in rats to ascertain the duration of action and insurmountability of MCAM in several relevant preparations. Reversal of μ opioid receptor agonist- (morphine and fentanyl) induced respiratory depression will be evaluated using whole body plethysmography. The relative duration of overdose protection afforded by MCAM versus naloxone will be measured in this preparation as well. Models of protection against opioid abuse will utilize measures of the reinforcing effects of the μ opioid receptor agonist remifentanil. The relative insurmountability and duration of action of MCAM versus naltrexone (currently used to treat abuse) in blocking the reinforcing effects of remifentanil will be established in this preparation. The smallest dose of MCAM that is effective when given daily in preventing the reinforcing effects of remifentanil will provide information on the rate of delivery that would be appropriate in a sustained-release formulation of MCAM. Comparisons will also be made of the relative ability of MCAM versus naloxone to elicit withdrawal in opioid- dependent rats. Lastly, because current µ opioid analgesic drugs will not be effective if a long-acting antagonist (e.g., MCAM) is used to treat abuse and/or overdose, we will assess the feasibility of peripherally-restricted administration of kappa opioid receptor agonists for use as analgesic agents in the presence of MCAM. Activation of peripheral kappa opioid receptors that are expressed on peripheral pain-sensing neurons can produce a level of analgesia equivalent to that produced by a local anesthetic and therefore may be a good approach for the treatment of pain in individuals with long-term blockade of µ opioid receptor function. Together, this work will provide needed information about whether MCAM offers substantial advantage over naloxone and naltrexone in blocking or preventing the actions of opioid drugs of abuse.

Methocinnamox (MCAM) 是一种长效 µ-阿片受体拮抗剂，在以下方面可能具有明显的优势： 我们建议使用体外和评估 MCAM 来治疗阿片类药物过量和阿片类药物滥用障碍。 体内测量，比较 MCAM 与阿片类拮抗剂纳曲酮和纳洛酮的作用， 目前分别用于治疗滥用和过量。 药理学特性，包括结合动力学和滥用阿片类药物的不可克服性，将 将 MCAM 与其他阿片受体拮抗剂区分开来 在体外，我们将 MCAM 与其他阿片受体拮抗剂进行比较。 纳洛酮用于关联/解离动力学、阿片类激动剂（芬太尼、吗啡）的克服能力、 拮抗作用的持续时间（MCAM 是不可逆的吗？），并确定 MCAM 的药理特征 将在大鼠体内采取多种细胞信号传导途径以确定作用的持续时间和 几种相关制剂中 MCAM 的不可克服性 逆转μ阿片受体激动剂-（吗啡） 和芬太尼）引起的呼吸抑制将使用全身体积描记法进行评估。 在此制剂中还将测量 MCAM 相对于纳洛酮提供的过量保护的持续时间。 防止阿片类药物滥用的模型将利用μ阿片类药物受体的增强作用措施 激动剂瑞芬太尼 MCAM 与纳曲酮（目前）的相对不可克服性和作用持续时间 在这种制剂中将确定瑞芬太尼的增强作用（用于治疗滥用）。 每天给予有效防止瑞芬太尼增强作用的最小剂量的 MCAM 提供有关 MCAM 缓释制剂中适当的递送速率的信息。 还将比较 MCAM 与纳洛酮在阿片类药物中引起戒断的相对能力 最后，因为目前的μ阿片类镇痛药物如果是长效拮抗剂则不会有效。 （例如，MCAM）用于治疗滥用和/或过量，我们将评估外周限制的可行性 在存在 MCAM 激活的情况下施用 kappa 阿片受体激动剂作为镇痛剂。 外周痛觉神经元上表达的外周卡帕阿片受体可以产生一定水平的 镇痛效果相当于局部麻醉药产生的镇痛效果，因此可能是一种很好的方法 这项工作将共同治疗长期阻断μ阿片受体功能的个体的疼痛。 提供有关 MCAM 是否比纳洛酮和纳曲酮具有显着优势的所需信息 阻止或防止滥用阿片类药物的作用。

项目成果

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

• DOI: 10.1002/prp2.887
• 发表时间: 2021-12
• 期刊: Pharmacology research & perspectives
• 影响因子: 2.6
• 作者: Zamora JC;Smith HR;Jennings EM;Chavera TS;Kotipalli V;Jay A;Husbands SM;Disney A;Berg KA;Clarke WP
• 通讯作者: Clarke WP

Ligand-Dependent Reversal Kinetics of Mu Opioid Receptor Agonists by the Novel Antagonist, Methocinnamox.

新型拮抗剂 Methocinnamox 的 Mu 阿片受体激动剂的配体依赖性逆转动力学。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Smith,HudsonR;Chavera,TeresaS;Berg,KellyA;Clarke,WilliamP
• 通讯作者: Clarke,WilliamP