Development of Specific Mu Opioid Receptor Antagonists to Reverse the Acute and Chronic Toxicity of Fentanyls

开发特异性 Mu 阿片受体拮抗剂以逆转芬太尼的急性和慢性毒性

• 批准号: 10476705
• 负责人: YAN ZHANG
• 金额: $ 282.44万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476705
• 关键词: Acute; Adult; Affinity; Amines; Antidotes; Binding; Biochemistry; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Cell Line; Cessation of life; Characteristics; Chemicals; Chronic; Clinical Research; Clinical Trials; Cyclic GMP; Dangerousness; Development; Dose; Drug Kinetics; Drug Screening; Effectiveness; Family; Fatality rate; Female; Fentanyl; Formulation; Funding; Goals; Half-Life; In Vitro; Infusion procedures; Investigation; Lead; Libraries; Ligands; Methods; Molecular; Morphine; Mus; Naloxone; Naltrexone; Opiate Addiction; Opioid; Opioid Antagonist; Opioid Receptor; Opioid Receptor Binding; Outcome; Overdose; Overdose reversal; Patient Noncompliance; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Precipitation; Procedures; Production; Property; Proteins; Rattus; Reporting; Skeleton; Solubility; Structure; Testing; Time; Toxic effect; Urine; Ventilatory Depression; acute toxicity; addiction; analog; antagonist; aqueous; base; compare effectiveness; compliance behavior; computational chemistry; design; drug candidate; drug development; drug discovery; drug metabolism; fentanyl overdose; in silico; in vivo; male; mu opioid receptors; nalmefene; nanomolar; noradrenergic; novel; opioid abuse; opioid epidemic; opioid overdose; opioid use disorder; opioid withdrawal; pre-clinical; preclinical development; prevent; receptor; response; scale up; side effect; small molecule libraries; synthetic opioid

Project Summary This proposal is in response to PAR-20-092: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional). We propose to develop novel MOR antagonists carrying 1-phenethyl-N-phenylpiperidin-4-amine skeleton to effectively and specifically reverse the acute toxicity of fentanyl and its analogs. The fentanyls are a large family of synthetic opioids and are prominent on the list of opioid abuse and addiction due to the fact that some of them are up to 10,000-fold more potent than morphine. Because of their high potency and longer half-life than naloxone, the front-line treatment for fentanyl overdose, multiple infusions and high doses of naloxone may be required during reversal procedure. Another fentanyl addiction treatment, naltrexone, has been reported with patient non-compliance and unwanted side effects. Recently we have identified a novel molecular mechanism of fentanyl binding and activation on its target protein, the MOR, through systematic computational chemistry and biochemistry studies. More importantly, we identified a new fentanyl derivative, phenylfentanil, as a potent antagonist of the MOR. Phenylfentanil shares the same structural skeleton, i.e. 1-phenethyl-N-phenylpiperidin-4-amine, with fentanyl. It carries reasonably high affinity to the MOR and acts as a neutral antagonist on the receptor based on recent studies. Accordingly, we plan to apply these findings to further characterize phenylfentanil and its derivatives with similar pharmacological characteristics both in vitro and in vivo, and pursue preclinical development on these leads as novel reversal agents against the acute toxicity of fentanyl. In the UG3 phase, we plan to pursue two specific aims in order to define novel leads with reasonable potency and pharmacokinetics profiles as fentanyl reversal agents while in the UH3 phase, we propose to conduct IND-enabling studies on the most promising candidate and eventually file an IND with the FDA by the end of the funding period.

项目摘要 这项建议是对PAR-20-092：开发预防和治疗阿片类药物使用的药物的回应 疾病和过量用药(UG3/UH3)(临床试验可选)。我们建议开发新的MOR拮抗剂 携带1-苯乙基-N-苯基哌啶-4-胺骨架有效和特异地逆转急性毒性 芬太尼及其类似物。芬太尼是一大类合成阿片类药物，在 阿片类药物滥用和成瘾，因为其中一些药物的效力比吗啡高出10,000倍。 由于其效力高，半衰期长于纳洛酮，芬太尼过量的一线治疗， 在逆转过程中可能需要多次输注和高剂量的纳洛酮。另一种芬太尼 据报道，成瘾治疗纳曲酮存在患者不依从性和不良副作用。 最近我们发现了芬太尼与其靶蛋白结合并激活的一种新的分子机制， MOR，通过系统的计算化学和生物化学研究。更重要的是，我们发现 一种新的芬太尼衍生物，苯芬太尼，作为MOR的有效拮抗剂。苯芬太尼的情况也是如此 结构骨架，即1-苯乙基-N-苯基哌啶-4-胺，含芬太尼。它具有相当高的亲和力 根据最近的研究，它对MOR具有中性拮抗剂的作用。因此，我们计划 应用这些发现进一步表征具有相似药理作用的苯芬太尼及其衍生物 在体外和体内的特征，并在这些导联上进行临床前开发作为新的逆转 抗芬太尼急性毒性的药物。在UG3阶段，我们计划追求两个具体目标，以便 将具有合理效力和药代动力学特征的新先导定义为芬太尼翻转剂 在UH3阶段，我们建议对最有希望的候选者进行IND使能研究，并最终 在资助期结束前向FDA提交IND。