Brain-penetrant GPR88 agonists as novel therapeutics for opioid abuse

摘要 本申请是根据RFA-DA-22-031提交的，它描述了一项多学科的努力，以开发新的、 脑穿透性小分子GPR88激动剂减轻阿片类药物成瘾相关行为反应 药物和改善阿片类药物依赖者的戒断症状。GPR88是一种孤儿G蛋白 纹状体蛋白(间接途径)介质中集中表达的偶联受体(GPCR) 纹状体中的神经元(MSN)。最近在转基因小鼠中的观察表明，GPR88对 对纹状体阿片受体信号的抑制影响。在这一点和其他最近有希望的基础上 临床前观察，我们建议利用我们在阿片类药物使用的神经生物学机制方面的专业知识 疾病和小分子药物发现正式确认GPR88是治疗阿片类药物使用障碍的药物靶点 (OUD)并通过发现GPR88激动剂先导化合物建立一条前进的药物开发道路。我们会 利用我们建立的阿片类药物依赖的体内小鼠模型和Gpr88-/-小鼠以及 可用的GPR88药理工具。不幸的是，已发表的GPR88激动剂有限制 它们在体内的效用，并阻止它们发展为治疗学。为了解决这一缺陷，我们将开发 新的，有效的GPR88激动剂，性能优化，用于治疗阿片依赖。我们都很好 有能力完成这项任务。我们最近进行了GPR88高通量屏幕(HTS)，使用 创新的药用香草酮分析格式，并确定了一种新的化学支架，以SBI-‘2037为例 作为一个有效的GPR88激动剂。此外，我们已经开发了强大的基于细胞的分析(和适当的 计数器筛选)，以可靠地监测GPR88的功能及其对阿片受体的影响。利用这些资产， 我们将开展药物化学活动，以提高SBI-‘2037支架的效力和选择性 关键路径包括细胞分析，重点放在其在OUD中的效用，包括早期评估 吸收、分布、代谢和排泄(ADME)和脑渗透特性。为了增加 总体成功概率，我们打算再进行一次GPR88高温超导筛查活动，以寻找 一个或多个备份系列。我们已经为GPR88激动剂导联建立了一套严格的标准，并且只有 符合这一特征的化合物将进入静脉注射羟考酮自我有效性测试。 野生型和Gpr88基因敲除小鼠的给药程序。这项多学科研究计划充分利用了 关于我们致力于研究的团队独特的相关科学和药物发现专业知识，是 我们朝着开发GPR88激动剂作为促进戒酒的新疗法的最终目标迈出了第一步 在阿片类药物依赖者身上。

SUMMARY Submitted in response to RFA-DA-22-031, this application describes a multidisciplinary effort to develop novel, brain-penetrant, small-molecule GPR88 agonists to attenuate addiction-relevant behavioral responses to opioid drugs and ameliorate withdrawal syndrome in opioid-dependent individuals. GPR88 is an orphan G-protein coupled receptor (GPCR) with concentrated expression in striatopallidal (indirect pathway) medium spiny neurons (MSNs) in the striatum. Recent observations in transgenic mice demonstrate that GPR88 exerts an inhibitory influence over opioid receptor signaling in the striatum. Building on this and other recent promising preclinical observations, we propose to leverage our expertise in neurobiological mechanisms of opioid use disorders and small-molecule drug discovery to formally validate GPR88 as a drug target for opioid use disorders (OUD) and establish a drug development path forward by discovering GPR88 agonist lead compounds. We will leverage an in vivo murine model of opioid dependence we have developed and Gpr88-/- mice along with available GPR88 pharmacological tools. Unfortunately, published GPR88 agonists have limitations that restrict their utility in vivo and prevent their development into therapeutics. To address this short coming we will develop novel, potent GPR88 agonists with properties optimized for the treatment of opioid dependence. We are well positioned to accomplish this task. We recently conducted a GPR88 high throughput screen (HTS), using an innovative pharmacochaperone assay format, and identified a novel chemical scaffold exemplified by SBI-‘2037 as a validated GPR88 agonist. In addition, we have already developed robust cell-based assays (and appropriate counter-screens) to reliably monitor GPR88 function and its impact on opioid receptors. Leveraging these assets, we will conduct a medicinal chemistry campaign to increase potency and selectivity of the SBI-‘2037 scaffold with a critical path consisting of cellular assays focused on their utility in OUD that includes early assessment of absorption, distribution, metabolism and excretion (ADME) and brain penetration properties. To increase the overall probability of success, we intend to conduct an additional GPR88 HTS screening campaign in search of one or more back up series. We have established a stringent set of criteria for GPR88 agonist leads, and only compounds that match this profile will be advanced into efficacy testing in the intravenous oxycodone self- administration procedure in wild-type and Gpr88 knockout mice. This multidisciplinary research plan capitalizes on the uniquely relevant scientific and drug discovery expertise of our team of committed investigators and is an initial step towards our ultimate goal of developing GPR88 agonists as novel therapeutics to facilitate abstinence in opioid-dependent individuals.