Brain-penetrant GPR88 agonists as novel therapeutics for opioid abuse

脑渗透性 GPR88 激动剂作为阿片类药物滥用的新型疗法

• 批准号: 10517225
• 负责人: Michael Jackson
• 金额: $ 215.1万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517225
• 关键词: Abstinence; Address; Adrenergic Agonists; Agonist; Attenuated; Back; Behavioral; Biological Assay; Brain; Cells; Cellular Assay; Cessation of life; Chemicals; Corpus striatum structure; Critical Pathways; Development; Disease; Dopamine; Drug Targeting; Economic Burden; Epidemic; Excretory function; FDA approved; G-Protein-Coupled Receptors; Genetic; Goals; Health; Human; Individual; Interdisciplinary Study; Intravenous; Knockout Mice; Lead; Maintenance; Metabolism; Monitor; Motivation; Mus; Nature; Neurons; Opiate Addiction; Opioid; Opioid Receptor; Opioid agonist; Orphan; Overdose; Oxycodone; Pathway interactions; Penetration; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Positioning Attribute; Probability; Procedures; Process; Property; Publishing; Receptor Signaling; Research; Research Personnel; Scientist; Self Administration; Series; Signal Transduction; Societies; Solubility; Structure-Activity Relationship; Substance Withdrawal Syndrome; Testing; Therapeutic; Time; Transgenic Mice; United States; Validation; Withdrawal Symptom; absorption; addiction; antagonist; associated symptom; base; behavioral response; drug development; drug discovery; efficacy study; efficacy testing; experience; high throughput screening; illicit opioid; improved; in vivo; innovation; meetings; mouse model; multidisciplinary; neurobiological mechanism; new therapeutic target; non-opioid analgesic; novel; novel therapeutics; opioid abuse; opioid mortality; opioid use; opioid use disorder; opioid withdrawal; pre-clinical; premature; prescription opioid; prevent; programs; reduce symptoms; response; scaffold; screening; small molecule; success; targeted treatment; tool; transmission process; treatment optimization

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.

概括 该应用程序是针对RFA-DA-22-031提交的，描述了开发小说的多学科工作， 脑培训剂，小分子GPR88激动剂，以减轻与成瘾相关的行为反应 阿片类药物依赖性个体的药物和改善戒断综合征。 GPR88是孤儿G蛋白 偶联受体（GPCR），在纹状体（间接途径）培养基中具有浓缩表达 纹状体中的神经元（MSN）。转基因小鼠的最新观察结果表明，GPR88导出了 纹状体中阿片受体信号传导的抑制作用。以此为基础和其他最近的承诺 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验证GPR88作为阿片类药物使用障碍的药物靶标 （OUD）并通过发现GPR88激动剂铅化合物来建立前进的药物开发路径。我们将 利用我们开发的阿片类药物依赖性体内鼠模型，以及GPR88 - / - 小鼠 可用的GPR88制药工具。不幸的是，已发表的GPR88激动剂有限制的局限性 他们在体内的效用，并防止其发展进入治疗。为了解决这个简短的到来，我们将发展 具有优化特性的新型GPR88激动剂，可用于治疗阿片类药物依赖性。我们很好 有助于完成这项任务。我们最近使用一个GPR88高通量屏幕（HTS）进行了 创新的药物马acchaperone分析格式，并确定了SBI-'2037例证的新型化学支架 作为经过验证的GPR88激动剂。此外，我们已经开发了强大的基于细胞的测定法（并且适当 反屏幕）可靠地监测GPR88功能及其对阿片类药物受体的影响。利用这些资产， 我们将开展一项医学化学运动，以提高SBI-'2037脚手架的效力和选择性 临界路径由蜂窝评估组成，重点是其在OUD中的效用，其中包括早期评估 抽象，分布，代谢和排泄（ADME）和脑渗透特性。增加 成功的总体可能性，我们打算进行额外的GPR88 HTS筛选活动以寻找 一个或多个备份系列。我们已经为GPR88激动剂铅建立了一套严格的标准，只有 匹配该轮廓的化合物将在静脉注射羟考酮自我的效率测试中提出 野生型和GPR88敲除小鼠的给药程序。这个多学科研究计划大写 关于我们承诺的调查人员团队的独特相关科学和药物发现专业知识，是一个 朝着我们开发GPR88激动剂作为促进戒酒的新疗法的最终目标的第一步 在阿片类药物依赖的个体中。