Mu Opioid Receptor Modulator Development to Treat Opioid Use Disorder

项目摘要 美国目前正处于阿片类药物危机中，NIDA致力于研究其机制和 阿片类药物使用障碍的治疗。目前美国食品和药物管理局批准的药物疗法 阿片类药物使用障碍包括MOR激动剂美沙酮、MOR部分激动剂丁丙诺啡和 MOR拮抗剂纳曲酮。然而，由于各种原因，这三种化合物的临床应用都受到了限制。 因此，开发新的、有效的、提高疗效的候选药物势在必行。 并减少不良影响。最近，我们发现了几个具有高度选择性和效力的更多 调节剂作为阿片类药物使用障碍治疗的新先导。它们都显示出更有希望的药理作用 与这一类别的其他已知药物比较的概况。目前的提案将侧重于进一步 开发这些用于临床前IND使能研究和动态药物发现和开发的线索 管道建设。该项目将分两个阶段实现四个综合的具体目标。在UG3中 阶段，我们将1)通过自我给药和PK进一步验证当前导联的治疗概况 2)扩大小分子文库，建立一个动态的药物发现和开发管道。 在UH3阶段，我们将1)对UH3阶段确定的铅(S)进行临床前IND使能研究， 2)比较UG3期和UG3期新HITS的体内药代动力学和药效学特征 当前的铅定义了我们的下一代铅化合物(S)。

Project Summary The United States is currently in an opioid crisis, and NIDA is committed to research on the mechanisms and treatment of opioid use disorder. Current Food and Drug Administration-approved pharmacotherapies for opioid use disorder include the MOR agonist methadone, the MOR partial agonist buprenorphine, and the MOR antagonist naltrexone. However, the clinical utility of all three compounds is limited for various reasons. Therefore, it is imperative to develop novel and effective drug candidates with enhanced therapeutic effects and reduced undesirable effects. Recently, we have identified several highly selective and potent MOR modulators as novel leads for opioid use disorder treatment. They all showed more promising pharmacological profiles compared to other known drugs in this category. The current proposal will focus on further development of these leads for preclinical IND-enabling studies, and dynamic drug discovery and development pipeline construct. Four integrated specific aims will be pursued in this project in two phases. In the UG3 phase, we will 1) further Validate therapeutic profiles of the current leads with self-administration and PK studies, and 2) expand the small molecule library to build a dynamic drug discovery and development pipeline. In the UH3 phase, we will 1) conduct preclinical IND-enabling studies on the lead(s) identified from UG3 phase, and 2) compare in vivo pharmacokinetics and pharmacodynamics profiles of the new hits from UG3 phase with current leads to define our next generation of lead compound(s).