Development of novel therapeutics for opioid dependence

项目摘要 本申请是为了响应RFA-DA-19-002，预防和治疗药物的开发而提交的 阿片类药物使用障碍和过量（UG 3/UH 3）。该应用程序描述了一个高度集成的项目， 开发新的Gpr 151拮抗剂以促进阿片类药物依赖个体的长期戒断。Gpr151 是一种孤儿G蛋白偶联受体（GPCR），几乎只在内侧缰核中表达。在 令人兴奋的新数据，我们证明，Gpr 151共定位与μ阿片受体在内侧缰， 这种孤儿受体调节阿片类药物对缰神经元的抑制作用。此外，我们显示 Gpr 151在调节阿片类药物（如吗啡）的动机特性方面起着关键作用， 羟考酮具体地说，我们发现Gpr 151无效突变的小鼠（Gpr 151-/-小鼠）对 并自我给予较少量羟考酮。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， 鉴定和优化用于治疗人类阿片样物质依赖的新型Gpr 151拮抗剂。作为Gpr 151 是一种孤儿受体，没有已知的配体，缺乏有效的激动剂可能会阻碍 鉴定新拮抗剂。然而，我们现在已经开发了稳健的基于细胞的测定（和适当的 counter-screens）来可靠地监测Gpr 151功能，并使用这些测定来鉴定新的Gpr 151激动剂。 在本申请的UG 3阶段，我们将优化这一系列激动剂，以提高其效力， Gpr 151的选择性（12个月）。一旦优化，我们将使用该系列中的强效和选择性激动剂， 有助于鉴定衍生自相同或相关化学系列的Gpr 151处的新拮抗剂 （主要策略）或通过高通量筛选（备用策略）（12个月）。新Gpr 151的鉴定 对抗者将触发该项目向UH 3阶段的过渡。在UH 3阶段，我们将采用 基于构效关系（SAR）的迭代药物化学，以优化效价， 新型Gpr 151受体拮抗剂的选择性。SAR还将用于优化这些拮抗剂的药物活性。 代谢和药代动力学（DMPK）和脑渗透特性，并确定那些最少 可能对人体有毒性。我们将评估那些具有最有利的药物样的影响， 阿片类药物对内侧缰核电生理反应的影响。另外我们 将使用静脉内羟考酮自我给药评估这些新拮抗剂的体内功效， 在野生型和Gpr 151-/-小鼠中恢复熄灭的应答程序。这种多学科 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， 致力于研究人员开发新的治疗方法，以促进阿片类药物依赖者的戒断。

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.