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

摘要 目前，临床上使用的药物滥用药物用于治疗鸦片类药物、酒精和尼古丁成瘾， 但不包括精神刺激剂，如冰毒(冰毒)。共同激活两种伤害素的化合物 阿片肽(NOP)和MU受体具有治疗药物滥用的潜力。尤其是丁丙诺啡， 部分Mu激动剂/kappa拮抗剂在NOP中也起低亲和力和部分激动剂的作用，被用作 阿片类药物使用障碍药物，并已显示出镇痛特性和疗效，在减少可卡因和 酒精消费，据报道是通过它对NOP受体的功效。随着NOP受体激活减少 Mu激活诱导奖赏，设计开发具有Mu/NOP双功能活性的新分子 减少滥用倾向和提高疗效的化合物作为治疗药物使用障碍的潜在药物 与丁丙诺啡相比。在一系列结构上相关的混合化合物中，菲尼克斯制药实验室 已经批准了一系列具有NOP/MU双功能活性的化合物。两个配体PPL-138和PPL-143是 显示出最高的NOP受体亲和力和效力，其中PPL-143显示出最大的疗效 没有。和丁丙诺啡一样，这两个化合物对Mu受体和高亲和力都有高亲和力和低药效。 和kappa受体的拮抗剂活性。一氧化氮合酶受体激动剂此前已被证实可阻断 冰毒条件性位置偏好。最近，我们发现PPL-138成功地降低了冰毒自身的含量。 大鼠给药。在这一应用中，我们建议进行动物实验来检查阿司匹林的安全性和有效性。 PPL-138和PPL-143作为治疗冰毒使用障碍(MUD)的候选药物并选择先导化合物 为了进一步的发展。具体目标1将评估这两种化合物在减少吸食冰毒方面的效果 长期接触冰毒的动物的冰毒行为和动机，这一过程密切反映了 泥巴的强迫性。由于复发是MUD的主要特征，因此也将对这两种化合物进行评估 因为他们有能力减少冰毒行为的恢复。这些实验将在两个地点进行 雄鼠和雌鼠。特定目标2将通过评估PPL-138和PPL-143的安全性来确定其安全性 增强性能和可能的公差发展。与前两个目标同时进行，具体目标3 将对PPL-143进行初步的药代动力学和ADME研究，这将整合行为学 结果。总的来说，本提案中计划的实验将决定是否增加NOP MU/NOP共激活的成分在疗效方面比丁丙诺啡有任何优势 和安全。这些实验也将为混合配体作为潜在泥浆的进一步发展提供信息。 药物治疗，选择先导化合物进行进一步开发，并为 关于NOP系统和冰毒领域的文献。

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.