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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要本申请是对 RFA-RM-19-011 的回应，旨在支持共同基金的试点项目 “照亮可药物基因组”(IDG) 计划，研究符合 IDG 资格的 GPCR、蛋白激酶、孤儿受体 GPR88 是一种符合 IDG 标准的 GPCR，在纹状体中具有强表达。多个证据表明 GPR88 发挥着重要作用。参与纹状体功能的调节，并与帕金森病等多种疾病有关，迄今为止，尚未发现 GPR88 的内源性配体。为了表征GPR88信号机制和生物学功能，我们课题组开展了我们最近开发了 GPR88 小分子激动剂探针的药物化学活动。第一个高效、选择性、脑渗透性 GPR88 激动剂 RTI-33，体内具有 GPR88 靶向然而，其药理学在减少大鼠和小鼠的饮酒和寻求行为方面具有活性。受体及其作用机制仍然很大程度上未知，因此限制了对其潜力的探索在这方面，目前尚无法获得的合适放射性配体将是一种强大的工具。用于配体-受体相互作用研究和放射自显影以绘制大脑中受体结合位点的图谱，它可用于预测受体的潜在功能并指导体内研究。优化并合成具有适当放射化学纯度和特异性的氚标记的 RTI-33 放射性配体在目标 2 中，我们将使用受体结合特性来表征受体结合特性。总的来说，完成这项资助将提供 GPR88。放射性配体服务 IDG 和研究界，以进一步表征 GPR88 系统。