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

• 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
• 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

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.

项目摘要 本提案是对特别关注通知（NOT-NS-20-030）的回应： 推动和拓展化学品医学对策的研究与开发 威胁我们计划继续开发新型和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样物质的威胁，即芬太尼及其类似物。 芬太尼是合成阿片类药物的一个大家族，在潜在化学威胁名单上很突出。 事实上，它们中的一些比吗啡的效力高出10，000倍，并且它们可以雾化或 放置在食物/水中使得使用它们的化学攻击的可能性变得真实的。设计师芬太尼 可以在单一位置合成，并且在街上很容易获得。由于其高效能和 半衰期长于纳洛酮，芬太尼过量的一线治疗，多次输注和高剂量 在逆转过程中可能需要纳洛酮。应急响应人员通常只有有限的 纳洛酮很容易被耗尽这些都可能导致更高的死亡率，如果人口众多， 攻击最近，我们发现了一种新的芬太尼结合和激活其靶点的分子机制 蛋白质，莫尔，通过系统的计算化学研究。因此，我们计划应用这些 基于苯基芬太尼的结构骨架设计新型莫尔调节剂的分子模拟发现， 莫尔的中性拮抗剂，并研究其特异性逆转芬太尼功能的潜力， 其类似物对莫尔的作用更有效和更特异。在完成这项试验计划后，我们计划 建立一个动态和持续的药物发现和开发管道，以对抗急性毒性， 鸦片威胁