Identification of Mixed NOP/mu partial agonists as lead compounds for treatment of methamphetamine use disorder

混合 NOP/mu 部分激动剂作为治疗甲基苯丙胺使用障碍的先导化合物的鉴定

• 批准号: 10577374
• 负责人: Andrea Cippitelli
• 金额: $ 32万
• 依托单位: PHOENIX PHARMALABS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-05-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577374
• 关键词: ADME Study; Adverse effects; Affinity; Agonist; Alcohol consumption; Alcohols; Analgesics; Animals; Behavior; Behavioral; Buprenorphine; Characteristics; Clinical; Cocaine; Development; Disease; Dose; Drug Kinetics; Drug abuse; Drug usage; Exposure to; Extinction; Family; Female; Future; Grant; Human; Husband; Investigation; Laboratories; Laboratory Animals; Laboratory Rat; Lead; Licensing; Ligands; Literature; Methamphetamine; Methamphetamine dependence; Methamphetamine use disorder; Modeling; Motivation; Naloxone; Nature; Nicotine; ORL1 receptor; Opioid; Opioid Peptide; Opioid Receptor; Peptide Receptor; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Preclinical Testing; Procedures; Property; Public Health; Rattus; Receptor Activation; Reinforcement Schedule; Relapse; Reporting; Research Priority; Rewards; Route; Safety; Self Administration; Series; Substance Use Disorder; System; Testing; Work; abuse liability; addiction; antagonist; behavior observation; clinical investigation; conditioned place preference; design; drug development; drug reward; effective therapy; efficacy evaluation; endophenotype; experimental study; fentanyl self-administration; human subject; kappa opioid receptors; kappa receptors; male; methamphetamine abuse; methamphetamine effect; methamphetamine exposure; methamphetamine user; mu opioid receptors; mu receptors; nociceptin; opioid use disorder; standard of care; substance use treatment

Abstract Currently, clinically used drug abuse medications exist for treatment of addiction to opiates, alcohol, and nicotine, but not psychostimulants, such as methamphetamine (METH). Compounds that co-activate both nociceptin opioid peptide (NOP) and mu receptors have potential for treatment of drug abuse. In particular, buprenorphine, a partial mu agonist/kappa antagonist, which also acts as a low affinity and partial agonist at NOP, is used as an opioid use disorder medication and has demonstrated analgesic properties and efficacy in reducing cocaine and alcohol consumption, reportedly through its efficacy at NOP receptors. As NOP receptor activation reduces reward induced by mu activation, new molecules with bifunctional mu/NOP activities were designed to develop compounds with reduced abuse liability and increased efficacy as potential treatment for substance use disorder as compared to buprenorphine. Among a family of structurally related mixed compounds, Phoenix PharmaLabs has licensed a series of compounds with bifunctional NOP/mu activity. Two ligands, PPL-138 and PPL-143, were shown to have the highest NOP receptor affinity and potency, with PPL-143 showing the greatest efficacy for NOP. Like buprenorphine, the two compounds have high affinity and low efficacy at mu receptors and high affinity and antagonist activity at kappa receptors. NOP receptor agonists have previously been demonstrated to block METH conditioned place preference. Recently, we found that PPL-138 successfully decreases METH self- administration in rats. In this application, we propose animal studies to examine the safety and the efficacy of PPL-138 and PPL-143 as candidate medications for METH use disorder (MUD) and to choose a lead compound for further development. Specific Aim 1 will assess the efficacy of both compounds in reducing METH-taking behavior and motivation for METH in animals exposed to long METH access, a procedure that closely reflects the compulsive nature of MUD. As relapse is a central feature of MUD, the two compounds will also be evaluated for their ability to reduce reinstatement of METH-seeking behavior. These experiments will be conducted both in male and female rats. Specific Aim 2 will determine safety of PPL-138 and PPL-143 by evaluating their reinforcing properties and possible tolerance development. Concurrently to the first two aims, Specific Aim 3 will conduct preliminary pharmacokinetic and ADME studies on PPL-143, which will integrate the behavioral results. Collectively, the experiments planned in the present proposal will determine whether increasing the NOP component in the context of a mu/NOP co-activation has any advantages over buprenorphine in terms of efficacy and safety. These experiments will also inform on further development of the mixed ligands as potential MUD pharmacotherapies, choose a lead compound for further development, and provide an important contribution to the literature of the NOP system and the METH addiction fields.

摘要 目前，临床上使用的药物滥用药物用于治疗阿片类药物、酒精和尼古丁成瘾， 但不是精神兴奋剂，如甲基苯丙胺（METH）。共激活伤害感受素 阿片肽（NOP）和μ受体具有治疗药物滥用的潜力。尤其是丁丙诺啡， 部分μ激动剂/κ拮抗剂也作为NOP的低亲和力和部分激动剂， 阿片样物质使用障碍药物，并已证明在减少可卡因和 酒精消耗，据报道，通过其对NOP受体的功效。随着NOP受体活化减少 由于mu激活诱导的奖赏，设计了具有双功能mu/NOP活性的新分子， 作为物质使用障碍的潜在治疗的具有降低的滥用倾向和增加的功效的化合物 与丁丙诺啡相比。在一系列结构相关的混合化合物中，Phoenix PharmaLabs 已批准了一系列具有双功能NOP/mu活性的化合物。两种配体PPL-138和PPL-143， 显示具有最高的NOP受体亲和力和效力，其中PPL-143显示出最大的功效， NOP.与丁丙诺啡一样，这两种化合物对mu受体具有高亲和力和低效力， 和对κ受体的拮抗剂活性。NOP受体激动剂先前已被证明阻断 METH条件性位置偏好。最近，我们发现PPL-138成功地降低了METH自 大鼠给药。在本申请中，我们建议进行动物研究，以检查 PPL-138和PPL-143作为METH使用障碍（MUD）的候选药物，并选择先导化合物 进一步发展。具体目标1将评估两种化合物在减少甲基苯丙胺摄入方面的疗效 长期接触METH的动物对METH的行为和动机，这一过程密切反映了 MUD的强迫性由于复发是MUD的主要特征，因此还将对这两种化合物进行评价。 因为他们有能力减少寻求冰毒行为的复发。这些实验将在 雄性和雌性大鼠。具体目标2将通过评估PPL-138和PPL-143的安全性来确定其安全性。 增强性能和可能的耐受性发展。与前两个目标同时，具体目标3 将对PPL-143进行初步的药代动力学和ADME研究，该研究将整合行为学 结果总的来说，本提案中计划的实验将决定是否增加NOP 在mu/NOP共活化的情况下，在功效方面， 和安全性这些实验也将为进一步开发混合配体作为潜在的MUD提供信息 药物治疗，选择一种先导化合物进行进一步开发，并为药物治疗提供重要贡献。 NOP系统和METH成瘾领域的文献。