Development of novel therapeutics for opioid dependence

项目总结 本申请是根据RFA-DA-19-002《预防和治疗药物的开发》提交的 阿片类药物使用障碍和过量(UG3/UH3)。该应用程序描述了一个高度集成的项目，旨在 开发新的GPR151拮抗剂以促进阿片类药物依赖者的长期戒断。GPR151 是一种孤儿G蛋白偶联受体，几乎只在内侧缰核表达。在……里面 令人兴奋的新数据，我们证明了GPR151与μ阿片受体共同定位于内侧缰核和 这种孤儿受体调节阿片类药物对缰核神经元的抑制作用。此外，我们还展示了 GPR151在调节阿片类药物的兴奋特性方面起着关键作用，如吗啡和 小鼠体内的羟考酮。特别是，我们发现GPR151零突变的小鼠(GPR151-/-小鼠)对 这些阿片类药物的刺激和奖励作用以及自我给药的羟考酮数量较少。在这里，我们 建议利用这一新知识，结合我们在小分子药物开发方面的专业知识， 寻找和优化治疗人类阿片依赖的新型GPR151拮抗剂。作为GPR151 是一种孤儿受体，目前尚不清楚其配体，缺乏有效的激动剂会阻碍 新型拮抗剂的鉴定。然而，我们现在已经开发了强大的基于细胞的分析(和适当的 反筛选)，以可靠地监测GPR151的功能，并使用这些分析来识别新的GPR151激动剂。 在这一应用的UG3阶段，我们将优化这一系列激动剂，以提高它们的效力和 GPR151的选择性(12个月)。一旦优化，我们将使用本系列中的有效和选择性激动剂来 促进GPR151上源自相同或相关化学系列的新拮抗剂的鉴定 (主要战略)或通过高通量筛选(后备战略)(12个月)。新基因GPR151的鉴定 拮抗剂将触发项目向UH3阶段的过渡。在UH3阶段，我们将聘请一名 基于构效关系(SAR)的迭代药物化学优化药效和 新型GPR151受体拮抗剂的选择性。合成孔径雷达也将用于优化这些拮抗剂的药物。 代谢和药物动力学(DMPK)和脑渗透特性，并找出最小的 可能对人体有毒性。我们将评估那些具有最有利药物类的药物的效果 内侧缰核对阿片类药物电生理反应的物理化学性质。此外，我们 将评估这些新型拮抗剂使用静脉注射羟考酮自我给药和 在野生型和GPR151-/-小鼠中恢复熄灭的反应程序。这是一个多学科的 研究计划将利用我们团队独特的相关科学和药物发现专业知识 致力于研究开发新的疗法，以促进阿片类药物依赖个人的戒断。

PROJECT SUMMARY This application is submitted in response to RFA-DA-19-002, Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3). The application describes a highly integrated project aimed at developing novel Gpr151 antagonists to facilitate long-term abstinence in opioid-dependent individuals. Gpr151 is an orphan G-protein coupled receptor (GPCR) that is expressed almost exclusively in the medial habenula. In exciting new data, we demonstrate that Gpr151 co-localizes with μ opioid receptors in the medial habenula and that this orphan receptor regulates the inhibitory effects of opioids on habenular neurons. Moreover, we show that Gpr151 plays a critical role in regulating the motivational properties of opioid drugs such as morphine and oxycodone in mice. Specifically, we find mice with null mutation in Gpr151 (Gpr151-/- mice) are resistant to the stimulant and rewarding effects of these opioids and self-administer lower quantities of oxycodone. Here, we propose to leverage this new knowledge, in conjunction with our expertise in small molecule drug development, to identify and optimize novel Gpr151 antagonists for the treatment of opioid dependence in humans. As Gpr151 is an orphan receptor for which there are no known ligands, the lack of potent agonists can hamper the identification of novel antagonists. However, we have now developed robust cell-based assays (and appropriate counter-screens) to reliably monitor Gpr151 function and used these assays to identify novel Gpr151 agonists. During the UG3 phase of this application, we will optimize this series of agonists to increase their potency and selectivity for Gpr151 (12 months). Once optimized, we will use potent and selective agonists from this series to facilitate the identification of novel antagonists at Gpr151 derived from the same or related chemical series (primary strategy) or via high-throughput screening (backup strategy) (12 months). Identification of novel Gpr151 antagonists will trigger the transition to the UH3 phase of the project. During the UH3 phase, we will employ an iterative medicinal chemistry based on structure-activity relationships (SAR) to optimize the potency and selectivity of novel Gpr151 receptor antagonists. SAR will also be used to optimize these antagonists for drug metabolism and pharmacokinetics (DMPK) and brain penetration properties, and identify those that are least likely to have toxicity in humans. We will assess the effects of those with the most favorable drug-like physiochemical properties on electrophysiological responses of medial habenula to opioid drugs. In addition, we will assess the in vivo efficacy these novel antagonists using the intravenous oxycodone self-administration and reinstatement of extinguished responding procedures in wild-type and Gpr151-/- mice. This multidisciplinary research plan will capitalize on the unique relevant scientific and drug discovery expertise of our team of committed investigators to develop novel therapeutics to facilitate abstinence in opioid-dependent individuals.