Preparation and characterization of radioligands for the orphan receptor GPR88

孤儿受体 GPR88 放射性配体的制备和表征

• 批准号: 10038885
• 负责人: David Hesk
• 金额: $ 22.02万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038885
• 关键词: Affinity; Agonist; Alcohol consumption; Anxiety; Area; Autoradiography; Award; Binding; Binding Proteins; Binding Sites; Biodistribution; Biological Assay; Biological Process; Brain; Childhood; Chorea; Collaborations; Communities; Computer Models; Corpus striatum structure; Cost Savings; Cyclic AMP; Disease; Dissociation; Dorsal; Drug Addiction; Drug Design; Funding; G-Protein-Coupled Receptors; Gene Expression Profiling; Genes; Genetic; Genetic Risk; Genetic study; Genome; Goals; Grant; High Pressure Liquid Chromatography; Human Genetics; I125 isotope; Immunohistochemistry; In Vitro; Investigation; Ion Channel; Kinetics; Knock-in; Knock-out; Knowledge; Label; Learning Disabilities; Licensing; Ligand Binding; Ligands; Link; Maps; Mediating; Mediation; Methods; Mus; Neurons; Orphan; Parkinson Disease; Pathway interactions; Pharmaceutical Chemistry; Pharmacology; Pilot Projects; Play; Positioning Attribute; Preparation; Property; Protein Kinase; Proteins; Radioactive; Radioactivity; Rattus; Regulation; Research; Rodent; Role; Schizophrenia; Shipping; Signal Pathway; Signal Transduction; Site; Speech Delay; Structure; Structure-Activity Relationship; System; Techniques; Therapeutic; Tritium; Variant; Venus; alcohol seeking behavior; analog; animal data; base; density; design; disorder risk; drug discovery; experience; experimental study; falls; genome resource; human data; improved; in vivo; insight; interest; new therapeutic target; novel; programs; radiochemical; radioligand; radiotracer; receptor; receptor binding; receptor function; response; scaffold; small molecule; tool

Project Summary This application is in response to RFA-RM-19-011, which aims to support pilot projects for the Common Fund Program "Illuminating the Druggable Genome" (IDG) to study IDG-eligible understudied GPCRs, protein kinases, and ion channels. The orphan receptor GPR88 is an IDG-eligible GPCR with robust expression in the striatum throughout the dorsal and ventral areas. Multiple lines of evidence suggest that GPR88 plays an important role in the regulation of striatal functions and is implicated in a number of disorders such as Parkinson’s disease, schizophrenia, anxiety, and drug addiction. To date, the endogenous ligand for GPR88 has not been discovered. In order to characterize GPR88 signaling mechanisms and biological functions, our group has carried out a medicinal chemistry campaign to develop GPR88 small-molecule agonist probes. We have recently developed the first highly potent, selective, and brain-penetrant GPR88 agonist RTI-33 that has GPR88 on-target in vivo activity in reducing alcohol drinking and seeking behaviors in rats and mice. However, the pharmacology of the receptor and its mechanism of action are still largely unknown, thus limiting exploration of its potential for therapeutic applications. In this regard, a suitable radioligand, that is currently unavailable, will be a powerful tool for ligand-receptor interactions studies and for autoradiography to map the receptor binding sites in the brain, which can be used to predict the potential functions of the receptor and guide in vivo studies. In Aim 1, we will optimize and synthesize tritium-labeled RTI-33 radioligands with suitable radiochemical purity and specific radioactivity for receptor binding studies. In Aim 2, we will characterize the receptor binding properties using saturation, kinetic, and competition binding experiments. Overall, completion of this grant will provide GPR88 radioligands to serve IDG and the research community in an effort to further characterize the GPR88 system.

项目摘要 本申请是对RFA-RM-19-011的回应，旨在支持共同基金的试点项目 计划“照亮可药用基因组”（IDG），研究IDG合格的未充分研究的GPCR，蛋白激酶， 和离子通道。孤儿受体GPR 88是在纹状体中具有稳健表达的IDG合格GPCR 遍布背部和腹部多条证据表明GPR 88在细胞凋亡中起重要作用。 在纹状体功能的调节中，并与许多疾病如帕金森病有关， 精神分裂症焦虑症和毒瘾迄今为止，尚未发现GPR 88的内源性配体。 为了表征GPR 88信号传导机制和生物学功能，我们的小组进行了一项研究。 药物化学活动，以开发GPR 88小分子激动剂探针。我们最近开发了 第一个高效的，选择性的，脑渗透性的GPR 88激动剂RTI-33，它在体内具有GPR 88的靶点 减少大鼠和小鼠的饮酒和寻找行为。然而， 受体及其作用机制在很大程度上仍然是未知的，因此限制了对其潜在的治疗作用的探索。 治疗应用。在这方面，一个合适的放射性配体，目前还没有，将是一个强大的工具 对于配体-受体相互作用的研究和用于绘制脑中受体结合位点的放射自显影， 其可用于预测受体的潜在功能并指导体内研究。在目标1中，我们 优化和合成具有合适放射化学纯度和特异性的氚标记的RTI-33放射性配体 受体结合研究的放射性。在目标2中，我们将使用以下方法表征受体结合特性： 饱和、动力学和竞争结合实验。总的来说，完成这项赠款将提供GPR 88 放射性配体服务于IDG和研究界，以进一步表征GPR 88系统。