Development of Agents for Synthetic Opioid Overdose

合成阿片类药物过量药物的开发

• 批准号: 10275603
• 负责人: THOMAS EDWARD PRISINZANO
• 金额: $ 45.9万
• 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/10275603
• 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; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Property; Rapid screening; Rattus; Recurrence; Reporting; Research; Research Personnel; Respiratory physiology; Risk; Route; Safety; Series; Serum; Site; Structure; Survivors; Testing; Therapeutic; Time; Toxic effect; Ventilatory Depression; Work; aerosolized; analog; 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.

芬太尼是一种合成阿片类药物，比吗啡高约100倍，用于 治疗疼痛，并适应麻醉。它也被认为是一种丧失能力的剂，一种化学物质 这会产生一种残疾状况，在暴露后数小时持续数小时，例如 意外的化学攻击。作为阿片类药物，芬太尼降低了中枢神经系统和呼吸系统 功能，可以通过呼吸道抑郁而致命。由于其效力很高，只摄入了几毫克 芬太尼或其他合成的Ooid可能对一个天真的个体致命。此外，在 一个与自由基础芬太尼类似物接触的化学攻击部位面临着生命的重大风险 - 威胁战术。 目前，市场上有三位阿片类拮抗剂有可能扭转 芬太尼，即纳洛酮，纳曲酮和纳米芬。最常用的是已批准的纳洛酮 通过多种路线进行给药，包括静脉内，肌内，皮下和鼻内。 但是，最近的报告表明，纳洛酮的剂量较高或重复剂量（由于复发 可能需要呼吸抑郁症来逆转芬太尼引起的呼吸抑郁症。这突出了 紧迫需要更有潜力和更长的作用阿片类药物拮抗剂，以对抗芬太尼诱导的呼吸道 沮丧。 先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。我们的核心假设是，纳曲酮的结构修饰将导致 新型的阿片类药物受体拮抗剂，具有芬太尼和相关类似物过量的潜力 具有高风险的个人。该提案的具体目的是（1）确定阿片类药物的拮抗剂 增强的药效和药代动力学特性； （2）确定并优化体内活性 小鼠中的卵毒剂，以及它们在逆转芬太尼在临床前模型中的影响方面的有效性 抗伤害感受，迭代使用AIM 1； （3）确定和优化阿片类拮抗剂在体内活性 大鼠，以及它们在逆转芬太尼和临床前模型中选定类似物的影响方面的有效性 阿片类药物诱导的运动和呼吸抑郁症，迭代为AIM 1。设计，合成，评估 这些分子中将对新的药理学问题的发展产生广泛的影响，这些问题旨在 与阿片类药物接收器的高效力和长时间相互作用。此信息将有助于身份证明 安全有效的疗法将在急性和意外暴露后拯救个人 芬太尼和相关类似物。