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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的目前，存在临床使用的药物滥用药物以治疗对阿片类药物，酒精和尼古丁的成瘾治疗，但不是精神刺激剂，例如甲基苯丙胺（甲基苯丙胺）。共同激活两种肉恶蛋白的化合物阿片肽（NOP）和MU受体具有治疗药物滥用的潜力。特别是丁丙诺啡，部分MU激动剂/Kappa拮抗剂，也用作NOP的低亲和力和部分激动剂，用作阿片类药物使用障碍药物药物，并且在减少可卡因和据报道，饮酒是通过其在NOP受体上的功效。随着NOP受体激活的减少 MU激活引起的奖励，具有双功能MU/NOP活性的新分子旨在发展作为药物使用障碍的潜在治疗方法，滥用责任降低并提高疗效的化合物与丁丙诺啡相比。在结构相关的混合化合物家族中，Phoenix PharmAlabs 已经许可了一系列具有双功能NOP/MU活性的化合物。两个配体PPL-138和PPL-143是证明具有最高的NOP受体亲和力和效力，PPL-143显示出最大的功效 nop。像丁丙诺啡一样，这两种化合物在MU受体和高亲和力方面具有高亲和力和低功效和Kappa受体的拮抗剂活性。 NOP受体激动剂以前已被证明可以阻止甲基调件的地方偏好。最近，我们发现PPL-138成功降低了甲基自我自我在大鼠中给药。在此应用中，我们提出了动物研究以检查的安全性和功效 PPL-138和PPL-143作为甲基甲基甲基苯丙胺使用障碍（MUD）的候选药物，并选择铅化合物为了进一步发展。具体目标1将评估两种化合物在减少甲基苯丙胺的功效暴露于长长甲基甲基甲基的动物中甲基苯丙胺的行为和动机，这一过程非常反映泥的强迫性。由于复发是泥浆的主要特征，因此也将评估两种化合物因为它们能够减少恢复寻求甲基苯丙胺的行为的能力。这些实验将在雄性和雌性老鼠。特定的目标2将通过评估PPL-138和PPL-143的安全性增强特性和可能的公差发展。同时达到前两个目标，特定目标3 将对PPL-143进行初步药代动力学和ADME研究，这将整合行为结果。总的来说，本提案中计划的实验将决定是否增加NOP 在MU/NOP共激活的背景下，组件在疗效方面具有比丁丙诺啡的优势和安全。这些实验还将告知混合配体作为潜在泥浆的进一步发展药物治疗，选择铅化合物进行进一步开发，并为 NOP系统和Meth成瘾领域的文献。