Novel fentanyl derivatives as counteracting agents against fentanyl

作为芬太尼对抗剂的新型芬太尼衍生物

基本信息

批准号：
10175594
负责人：
YAN ZHANG
金额：
$ 12.5万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10175594
关键词：
Acute Administrative Supplement Adult Affinity Amines Award Binding Biological Assay Cell Line Central Nervous System Agents Chemical Structure Chemical Warfare Chemicals Chronic Crystallization Dangerousness Development Dose Effectiveness Exposure to Family Fatality rate Female Fentanyl Food Funding Funding Mechanisms Goals Grant Half-Life In Vitro Infusion procedures Lead Life Location Molecular Morphine Mus Naloxone Opioid Opioid Antagonist Opioid Receptor Outcome Overdose Parents Pilot Projects Population Procedures Property Proteins Research Route Series Skeleton Structure Structure-Activity Relationship Testing Time Toxic effect United States National Institutes of Health Ventilatory Depression Water acute toxicity aerosolized analog base chemical synthesis chemical threat combat compare effectiveness computational chemistry design drug candidate drug development drug discovery emergency service responder in vivo interest male medical countermeasure molecular modeling mouse model mu opioid receptors novel opioid overdose opioid use disorder pharmacokinetics and pharmacodynamics radioligand receptor research and development response synthetic opioid therapy development

项目摘要

Project Summary This proposal is in response to the Notice of Special Interest (NOT-NS-20-030): Administrative Supplements to Promote and Expand into the Research and Development of Medical Countermeasures Against Chemical Threats. We plan to pursue the development of novel and potent fentanyl derivatives as mu opioid receptor (MOR) modulators to counteract the acute exposure to potent synthetic opioid threat, i.e. fentanyl and its analogs. The fentanyls are a large family of synthetic opioids and are prominent on the list of potential chemical threats. The fact that some of them are up to 10,000-fold more potent than morphine and they can be aerosolized or placed into food/water makes the potential of a chemical attack using them becoming real. Designer fentanyls can be synthesized at a single location and are readily available on the street. 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. Emergency responders often have a limited supply of naloxone, which could easily be depleted. All these may lead to higher fatality rate if a large population is under attack. Recently we have identified a novel molecular mechanism of fentanyl binding and activation on its target protein, the MOR, through systematic computational chemistry studies. Accordingly, we plan to apply these molecular modeling findings to design novel MOR modulators based on the structural skeleton of phenylfentanil, a neutral antagonist on the MOR, and to study their potential to specifically reverse the function of fentanyl and its analogs on the MOR more effectively and specifically. Following the completion of this pilot project, we plan to establish a dynamic and continuous drug discovery and development pipeline to combat the acute toxicity of the opioid threat.

项目概要本提案是对特别利益通知 (NOT-NS-20-030) 的回应：行政补充促进和扩大化学物质医学对策的研究和开发威胁。我们计划开发新型有效的芬太尼衍生物作为μ阿片受体 (MOR) 调节剂，以抵消急性暴露于强效合成阿片类药物（即芬太尼及其类似物）的威胁。芬太尼是合成阿片类药物的一个大家族，在潜在化学威胁清单中名列前茅。事实上，其中一些药物的效力比吗啡强 10,000 倍，并且可以雾化或雾化放入食物/水中使得使用它们进行化学攻击的可能性成为现实。设计师芬太尼可以在一个地点合成，并且在街上很容易获得。由于它们的高效能和比纳洛酮更长的半衰期，纳洛酮是芬太尼过量、多次输注和高剂量的一线治疗方法在逆转过程中可能需要纳洛酮。紧急救援人员的物资供应通常有限纳洛酮，很容易耗尽。如果大量人口处于这种状态，所有这些都可能导致更高的死亡率攻击。最近，我们发现了芬太尼结合和激活其靶标的新分子机制蛋白质，MOR，通过系统的计算化学研究。因此，我们计划应用这些分子建模结果设计基于苯芬太尼结构骨架的新型MOR调节剂， MOR 的中性拮抗剂，并研究它们特异性逆转芬太尼和它在 MOR 上的类似物更有效、更具体。该试点项目完成后，我们计划建立动态、连续的药物发现和开发管道，以对抗药物的急性毒性阿片类药物的威胁。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sex differences in the effect of chronic delivery of the buprenorphine analogue BU08028 on heroin relapse and choice in a rat model of opioid maintenance.

丁丙诺啡类似物 BU08028 长期给药对海洛因复吸的影响的性别差异以及阿片类药物维持大鼠模型的选择。

DOI：
发表时间：
2022
期刊：
影响因子：
7.3
作者：
Bossert, Jennifer M;Townsend, E Andrew;Altidor, Lindsay K;Fredriksson, Ida;Shekara, Aniruddha;Husbands, Stephen;Sulima, Agnieszka;Rice, Kenner C;Banks, Matthew L;Shaham, Yavin
通讯作者：
Shaham, Yavin