Development of Long Lasting Stable Fentanyl Antagonist to Reverse Opioid Overdose

项目摘要 与阿片类药物相关的过量死亡几乎占美国所有药物过量死亡的一半 而且每年造成的死亡人数比车祸还多，是可以预防的。芬太尼，一种高度 强有力的MU阿片受体(MOR)激动剂及其类似物(芬太洛)越来越多地被发现被切割 非法药物样本，在主要滥用药物是阿片类药物的情况下，以及在其 不是的。芬太洛在非法毒品市场的盛行被认为是导致 自2016年以来，与阿片类药物相关的过量死亡人数增加。标准阿片类药物过量抢救 治疗时，纳洛酮往往不足以逆转芬太洛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，纳洛酮要么无效，要么无效。 作用时间足够或太短，不能有效逆转芬太洛过量和 抢救病人。这项建议的目标是设计新型阿片类拮抗剂 芬太尼支架在芬太尼拮抗剂基础上的改进 药代动力学特性(新陈代谢受限、高血脑渗透率和快速 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吗啡紧密结合，并在体内表现出快速起效。 最重要的假设是芬太洛格支架上的拮抗剂将更有效 在阻止阿片类药物过量方面优于纳洛酮。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利拮抗剂阻断芬太尼诱导的抗伤害作用的能力 和呼吸抑制，并检测它们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，我们将在体外表征这两个 在活体内。总体而言，该项目将开发新的芬太洛拮抗剂用于阿片类药物的治疗 并对其体外和体内药理特性进行表征。

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.