Development of Agents for Synthetic Opioid Overdose

合成阿片类药物过量药物的开发

• 批准号: 10470923
• 负责人: THOMAS EDWARD PRISINZANO
• 金额: $ 45.01万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10470923
• 关键词: Acute; Adjuvant; Anesthesia procedures; Antidotes; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemical Warfare; Chemicals; Chemistry; Country; Development; Dose; Effectiveness; Evaluation; Event; Exposure to; FDA approved; Fentanyl; Gases; Generations; Goals; Half-Life; Hospitalization; Hostage; Hour; In Vitro; Individual; Ingestion; Inhalation Anesthetics; Intramuscular; Intravenous; Laboratories; Lead; Life; Metabolic; Military Personnel; Modification; Morphine; Moscow; Mus; Naloxone; Naltrexone; Neuraxis; Neuropharmacology; Opioid; Opioid Antagonist; Opioid Receptor; Pain management; Persons; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Property; Rapid screening; Rattus; Recurrence; Reporting; Research; Research Personnel; Respiratory physiology; Risk; Route; Safety; Series; Serum; Site; Survivors; Testing; Therapeutic; Time; Toxic effect; Ventilatory Depression; Work; aerosolized; analog; antagonist; base; carfentanil; combat; design; experience; experimental study; fentanyl overdose; first responder; follow-up; high risk; improved; in vivo; incapacitating agents; mass casualty; milligram; mouse model; nalmefene; noradrenergic; novel; opioid overdose; overdose death; pharmacokinetics and pharmacodynamics; subcutaneous; synthetic opioid; therapeutically effective; water solubility

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.

芬太尼是一种合成的阿片类药物，比吗啡强约100倍，用于 治疗疼痛，以及麻醉辅助剂。它也被认为是一种失能剂，一种化学物质， 在暴露发生后持续数小时至数天的禁用条件，例如在 意想不到的化学攻击作为阿片类药物，芬太尼抑制中枢神经系统和呼吸系统， 功能，并可致命的呼吸抑制。由于其高效力，摄入仅几毫克 芬太尼或其他合成阿片类药物可能对阿片类药物初治者致命。此外，第一反应者在 接触游离碱芬太尼类似物的化学攻击地点有重大生命危险- 毒性威胁 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、纳洛酮和纳美芬。最常用的是纳洛酮， 用于通过多种途径给药，包括静脉内、肌内、皮下和鼻内。 然而，最近的报告表明，较高剂量或重复给药纳洛酮（由于复发）， 呼吸抑制）可能需要逆转芬太尼诱导的呼吸抑制。这凸显 迫切需要一种更有效和更长效的阿片类拮抗剂来对抗芬太尼诱导的呼吸道疾病 萧条 以前的研究和我们自己的初步结果表明，纳洛酮的结构修饰可以增加 其效力和作用持续时间。我们的中心假设是纳洛酮的结构修饰将导致 具有治疗芬太尼和相关类似物过量的潜力的新型阿片受体拮抗剂 暴露风险高的人。该提案的具体目标是（1）确定阿片类拮抗剂， 增强的药效学和药代动力学性质;（2）确定和优化 阿片类拮抗剂在小鼠中的作用，以及它们在逆转芬太尼在临床前模型中的作用的有效性。 抗伤害感受，与Aim 1迭代;和（3）确定和优化阿片受体拮抗剂的体内活性， 大鼠，以及它们在临床前模型中逆转芬太尼和选定类似物的作用的有效性 阿片类药物诱导的运动和呼吸抑制，迭代目标1。设计、综合、评价 这些分子将对开发新的药理学探针产生广泛的影响， 与阿片受体高效力和长持续时间相互作用。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 芬太尼和相关类似物。