Development of Long Lasting Stable Fentanyl Antagonist to Reverse Opioid Overdose

项目摘要 在美国，与阿片类药物有关的过量死亡几乎占所有药物过量死亡的一半。 每年造成的可预防的死亡人数超过车祸。芬太尼，一种高度 有效的μ阿片受体（莫尔）激动剂及其类似物（芬太尼）越来越多地被发现切割 在主要滥用药物是阿片类药物的情况下， 并不自由芬太尼类药物在非法药物市场的流行被认为是 自2016年以来，阿片类药物过量死亡人数增加。标准阿片类药物过量救援 纳洛酮通常不足以逆转芬太尼激动剂引起的阿片类药物过量 在目前的治疗模式下。据报道，纳洛酮不是强效的， 足够或作用时间太短，无法有效逆转芬太尼过量， 使病人复苏。本提案的目的是设计新的阿片类药物拮抗剂， 芬太尼支架基于先前鉴定的芬太尼拮抗剂，并改善其 药代动力学特性（有限代谢、高血脑渗透和快速代谢） 吸收）相对于纳洛酮。我们认为芬太尼支架是一个很好的起点 因为芬太尼及其类似物已经与莫尔紧密结合并在体内显示出快速起效。 总体假设是芬太尼支架上的拮抗剂将更有效 比纳洛酮更有效我们将从两个方面探讨这一假设：1）我们 将检查两种主要芬太尼拮抗剂阻断芬太尼诱导的抗伤害感受的能力 和呼吸抑制，并检测其在整个动物体内的分布和代谢 模型和2）设计新的代谢稳定的类似物，我们将在体外表征 和体内。总体而言，本项目将开发用于治疗阿片类药物的新芬太尼拮抗剂 过量并表征其体外和体内药理学性质。

Project Abstract Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist, and its analogs (fentalogs) are increasingly found cut into illicit drug samples, both where the primary drug of abuse is an opioid and in cases where it is not. The prevalence of fentalogs in the illicit drug market is thought to be the primary driver of increased opioid-related overdose deaths since 2016. The standard opioid overdose rescue therapy, naloxone is often insufficient to reverse opioid overdoses caused by fentalog agonists under current treatment paradigms. It has been reported that naloxone is either not potent enough or has too short a duration of action to effectively reverse fentalog overdose and resuscitate patients. The objective of this proposal is to design novel opioid antagonists on the fentanyl scaffold based on previously identified fentalog antagonists and improve their pharmacokinetic properties (limited metabolism, high blood-brain penetration, and rapid absorption) relative to naloxone. We propose that the fentanyl scaffold is a good starting point as fentanyl and its analogs already bind tightly to MOR and display rapid onset of action in vivo. The overarching hypothesis is that antagonists on the fentalog scaffold will be more effective than naloxone in blocking opioid overdose. We will explore this hypothesis in two aims: 1) we will examine the ability of two lead fentalog antagonists to block fentanyl induced antinociception and respiratory depression and examine their distribution and metabolism in whole animal models and 2) design novel metabolically stable analogs which we will characterize both in vitro and in vivo. Overall, this project will develop new fentalog antagonists for the treatment of opioid overdose and characterize their in vitro and in vivo pharmacological properties.