Development of Agents for Synthetic Opioid Overdose

芬太尼是一种合成阿片类药物，强度约为吗啡的100倍，用于 治疗疼痛，以及麻醉的辅助剂。它也被认为是一种致残剂，一种化学物质 这会产生一种在暴露发生后持续数小时到数天的禁用状态，例如在 意外的化学攻击。作为一种阿片类药物，芬太尼抑制中枢神经系统和呼吸 功能，并可能是致命的呼吸抑制。由于它的高效力，只摄入几毫克 芬太尼或其他合成阿片类药物对阿片类药物天真的人来说可能是致命的。此外，现场的急救人员 接触游离碱芬太尼类似物的化学攻击场所有极大的生命危险- 有威胁的毒物。 目前，市场上有三种阿片类拮抗剂，它们有可能逆转 芬太尼，即纳洛酮、纳曲酮和纳美芬。最常用的是批准的纳洛酮 通过多种途径给药，包括静脉、肌肉、皮下和鼻腔给药。 然而，最近的报告表明，较高剂量或重复剂量的纳洛酮(由于复发) 呼吸抑制)可能需要逆转芬太尼引起的呼吸抑制。这突出了 迫切需要一种更有效和更长效的阿片拮抗剂来对抗芬太尼诱导的呼吸 抑郁症。 以前的研究和我们自己的初步结果表明，纳曲酮的结构修饰可以增加 它的效力和行动持续时间。我们的中心假设是纳曲酮的结构修饰将导致 新型阿片受体拮抗剂对芬太尼及其类似物过量的治疗作用 处于高暴露风险的个人。这项建议的具体目的是(1)识别阿片类拮抗剂 增强的药效学和药代动力学性质；(2)测定和优化其体内活性 阿片类拮抗剂在小鼠中的作用，以及它们在临床前模型中逆转芬太尼的作用的有效性 抗伤害性，迭代与目标1；和(3)确定和优化阿片类拮抗剂在体内的活性 大鼠，以及它们在临床前模型中逆转芬太尼及其部分类似物作用的有效性 阿片类药物诱导的运动和呼吸抑制，反复，目的1.设计，合成，评价 这些分子将对开发新的药物探针产生广泛的影响，这些探针旨在 与阿片受体的高效力和长时间相互作用。这些信息将有助于识别 安全有效的治疗方法，可以在急性和意外暴露于 芬太尼及其类似物。

Fentanyl is a synthetic opioid that is approximately 100 times stronger than morphine and is used for the treatment of pain, as well as an adjuvant for anesthesia. It is also considered an incapacitating agent, a chemical that produces a disabling condition that persists for hours to days after exposure has occurred, such as in an unexpected chemical attack. As an opioid, fentanyl depresses the central nervous system and respiratory functions, and can be lethal by respiratory depression. Due to its high potency, ingestion of just a few milligrams of fentanyl or other synthetic opioid can be deadly to an opioid naïve individual. Furthermore, first responders at a chemical attack site who come in contact with free base fentanyl analogues are at significant risk for life- threatening toxicities. Currently, there are three opioid antagonists available on the market that have potential to reverse the effects of fentanyl, namely naloxone, naltrexone, and nalmefene. The most commonly used is naloxone which is approved for administration by a variety of routes, including intravenous, intramuscular, subcutaneous and intranasal. However, recent reports suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fentanyl-induced respiratory depression. This highlights the pressing need for a more potent and longer acting opioid antagonist to combat fentanyl-induced respiratory depression. Previous studies and our own preliminary results indicate that structural modification of naltrexone can increase its potency and duration of action. Our central hypothesis is that structural modification of naltrexone will lead to novel opioid receptor antagonists with the potential to treat overdose by fentanyl and related analogues in individuals at high risk of exposure. The specific aims of this proposal are (1) identify opioid antagonists with enhanced pharmacodynamic and pharmacokinetic properties; (2) determine and optimize the in vivo activity of opioid antagonists in mice, and for their effectiveness in reversing the effects of fentanyl in preclinical models of antinociception, iteratively with Aim 1; and (3) determine and optimize the in vivo activity of opioid antagonists in rats, and for their effectiveness in reversing the effects of fentanyl and selected analogues in preclinical models of opioid-induced locomotor and respiratory depression, iteratively with Aim 1. The design, synthesis, evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with high potency and long duration at opioid receptors. This information will facilitate the identification of safe and effective therapeutics that would rescue individuals after an acute and unexpected exposure to fentanyl and related analogues.