Development of Agents for Synthetic Opioid Overdose

合成阿片类药物过量药物的开发

• 批准号: 10672919
• 负责人: THOMAS EDWARD PRISINZANO
• 金额: $ 44.42万
• 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/10672919
• 关键词: Acute; Adjuvant; Anesthesia procedures; Antidotes; Centers for Disease Control and Prevention (U.S.); Central Nervous System; 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; Marketing; Metabolic; Military Personnel; Modification; Morphine; Moscow; Mus; Naloxone; Naltrexone; Neuropharmacology; Opioid; Opioid Antagonist; Opioid Receptor; Pain management; Persons; Pharmaceutical Preparations; Pre-Clinical Model; Property; Rapid screening; Rattus; Recurrence; Reporting; Research; Research Personnel; Respiratory physiology; Risk; Route; Safety; Series; Serum; Site; Survivors; Testing; Therapeutic; Toxic effect; Ventilatory Depression; Work; aerosolized; analog; antagonist; antinociception; base; carfentanil; combat; design; experience; experimental study; fentanyl analog; fentanyl exposure; 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; pharmacologic; skills; subcutaneous; success; 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，其强度约为吗啡的 100 倍，用于治疗 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 会产生一种在接触后持续数小时至数天的致残状况，例如在 意外的化学袭击。作为阿片类药物，芬太尼会抑制中枢神经系统和呼吸系统 功能，并可因呼吸抑制而致命。由于其效力高，只需摄入几毫克 芬太尼或其他合成阿片类药物对于未使用阿片类药物的人来说可能是致命的。此外，急救人员 接触游离碱芬太尼类似物的化学攻击地点将面临重大生命危险- 威胁毒性。 目前，市场上有三种阿片拮抗剂，有可能逆转阿片类药物的影响 芬太尼，即纳洛酮、纳曲酮和纳美芬。最常用的是经批准的纳洛酮 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，更高剂量或重复服用纳洛酮（由于复发） 呼吸抑制）可能需要逆转芬太尼引起的呼吸抑制。这凸显了 迫切需要一种更有效、作用更持久的阿片类拮抗剂来对抗芬太尼引起的呼吸系统疾病 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 它的效力和作用持续时间。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，具有治疗芬太尼和相关类似物过量的潜力 暴露风险高的个人。该提案的具体目标是（1）确定阿片类拮抗剂 增强药效学和药代动力学特性； (2) 测定并优化其体内活性 阿片类拮抗剂在小鼠体内的作用，以及它们在临床前模型中逆转芬太尼作用的有效性 抗伤害，与目标 1 迭代； (3) 确定并优化阿片类拮抗剂的体内活性 大鼠，及其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 阿片类药物引起的运动和呼吸抑制，与目标 1 迭代。设计、合成、评估 这些分子的研究将对新药理学探针的开发产生广泛的影响，这些探针旨在 与阿片受体相互作用，效果高效且持续时间长。此信息将有助于识别 安全有效的治疗方法可以在急性和意外暴露后拯救个体 芬太尼及相关类似物。

项目成果

Potent MOR Agonists from 2'-Hydroxy-5,9-dimethyl-N-phenethyl Substituted-6,7-benzomorphans and from C8-Hydroxy, Methylene and Methyl Derivatives of N-Phenethylnormetazocine.

• DOI: 10.3390/molecules28237709
• 发表时间: 2023-11-22
• 期刊: Molecules (Basel, Switzerland)
• 作者: Das M;Ward GW;Sulima A;Luo D;Prisinzano TE;Imler GH;Kerr AT;Jacobson AE;Rice KC
• 通讯作者: Rice KC

A Journey through Diastereomeric Space: The Design, Synthesis, In Vitro and In Vivo Pharmacological Activity, and Molecular Modeling of Novel Potent Diastereomeric MOR Agonists and Antagonists.

• DOI: 10.3390/molecules27196455
• 发表时间: 2022-09-30
• 期刊: Molecules (Basel, Switzerland)
• 作者: Chambers DR;Sulima A;Luo D;Prisinzano TE;Goldberg A;Xie B;Shi L;Paronis CA;Bergman J;Nassehi N;Selley DE;Imler GH;Jacobson AE;Rice KC
• 通讯作者: Rice KC

Discovery of a Potent Highly Biased MOR Partial Agonist among Diastereomeric C9-Hydroxyalkyl-5-phenylmorphans.

• DOI: 10.3390/molecules28124795
• 发表时间: 2023-06-15
• 期刊: MOLECULES
• 影响因子: 4.6
• 作者: Lutz, Joshua A.;Sulima, Agnieszka;Gutman, Eugene S.;Bow, Eric W.;Luo, Dan;Kaska, Sophia;Prisinzano, Thomas E.;Paronis, Carol A.;Bergman, Jack;Imler, Gregory H.;Kerr, Andrew T.;Jacobson, Arthur E.;Rice, Kenner C.
• 通讯作者: Rice, Kenner C.

Synthesis and Pharmacological Evaluation of Enantiopure N-Substituted Ortho-c Oxide-Bridged 5-Phenylmorphans.

• DOI: 10.3390/molecules27248808
• 发表时间: 2022-12-12
• 期刊: Molecules (Basel, Switzerland)
• 作者: Li F;Kopajtic TA;Katz JL;Luo D;Prisinzano TE;Imler GH;Deschamps JR;Jacobson AE;Rice KC
• 通讯作者: Rice KC

A MOR Antagonist with High Potency and Antagonist Efficacy among Diastereomeric C9-Alkyl-Substituted N-Phenethyl-5-(3-hydroxy)phenylmorphans.

• DOI: 10.3390/molecules28145411
• 发表时间: 2023-07-14
• 期刊: Molecules (Basel, Switzerland)