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， 阿片类药物使用障碍的治疗。目前食品和药物管理局批准的药物治疗 阿片类药物使用障碍包括莫尔激动剂美沙酮，莫尔部分激动剂丁丙诺啡，和 莫尔拮抗剂纳洛酮。然而，由于各种原因，所有三种化合物的临床效用受到限制。 因此，开发具有增强的治疗效果的新颖且有效的候选药物势在必行 并且减少了不期望的效果。最近，我们已经确定了几个高度选择性和有效的莫尔 调节剂作为阿片类药物使用障碍治疗的新先导物。它们都显示出更有前途的药理学作用， 与该类别中的其他已知药物相比。目前的建议将侧重于进一步 为临床前IND研究开发这些线索，以及动态药物发现和开发 管道建设该项目将分两个阶段实现四个综合具体目标。在UG3 阶段，我们将1）通过自我给药和PK进一步验证当前电极导线的治疗特征 研究，以及2）扩大小分子库，以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UG3阶段确定的电极导线进行临床前IND使能研究， 和2）比较来自UG3期的新命中物的体内药代动力学和药效学特征， 目前的铅来定义我们的下一代铅化合物。

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).