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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该提案是对 PAR-20-092 的回应：开发预防和治疗阿片类药物使用的药物疾病和药物过量 (UG3/UH3)（临床试验可选）。我们建议开发新型 MOR 拮抗剂携带1-苯乙基-N-苯基哌啶-4-胺骨架，有效特异性逆转急性毒性芬太尼及其类似物。芬太尼是合成阿片类药物的一个大家族，在名单上很突出。阿片类药物滥用和成瘾，因为其中一些药物的效力比吗啡强 10,000 倍。由于其效力比纳洛酮（芬太尼过量的一线治疗方法）更长且半衰期更长，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，成瘾治疗纳曲酮会导致患者不依从并产生不良副作用。最近，我们发现了芬太尼与其靶蛋白结合和激活的新分子机制， MOR，通过系统的计算化学和生物化学研究。更重要的是，我们确定了一种新的芬太尼衍生物，苯芬太尼，作为 MOR 的有效拮抗剂。苯芬太尼有相同的作用结构骨架，即1-苯乙基-N-苯基哌啶-4-胺，带有芬太尼。它具有相当高的亲和力根据最近的研究，MOR 可以作为受体的中性拮抗剂。因此，我们计划应用这些发现进一步表征苯芬太尼及其具有相似药理作用的衍生物体外和体内的特征，并以这些先导药物为基础进行临床前开发，作为新的逆转抗芬太尼急性毒性的药物。在 UG3 阶段，我们计划实现两个具体目标定义具有合理效力和药代动力学特征的新先导药物作为芬太尼逆转剂在 UH3 阶段，我们建议对最有希望的候选者进行 IND 支持研究，并最终在资助期结束前向 FDA 提交 IND 申请。