Discovery and development of GPR3 agonists for nicotine cessation

发现和开发用于戒烟的 GPR3 激动剂

基本信息

批准号：
10825123
负责人：
CHRISTIE D FOWLER
金额：
$ 87.89万
依托单位：
RESEARCH TRIANGLE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10825123
关键词：
Acceleration Agonist Animal Model Arrestins Attenuated Behavior Behavioral Behavioral Model Biological Biological Assay Brain region Cause of Death Cells Central Nervous System Chemicals Computer Models Consumption Cryoelectron Microscopy Cyclic AMP Descriptor Development Disease Docking Dose Drug Delivery Systems Effectiveness Family Family member Female Filtration G-Protein-Coupled Receptors GPR12 gene GPR3 gene GPR6 gene Goals Grant Habenula Health In Vitro Individual Intake Intravenous Knockout Mice Lead Ligand Binding Ligands Link Medial Modeling Motivation Mus Nicotine Nicotine Dependence Nicotinic Agonists Nicotinic Receptors Opioid Receptor Orphan Pathway interactions Pattern Pharmaceutical Chemistry Pharmaceutical Preparations Phosphorylation Principal Component Analysis Process Property Psychological reinforcement Rattus Receptor Activation Research Role Self Administration Signal Transduction Site Structure Structure-Activity Relationship Substance Use Disorder Substance abuse problem System Testing Therapeutic Tobacco Dependence Tobacco Use Disorder Validation Wild Type Mouse Withdrawal analog behavior measurement brain cell brain pathway cannabinoid receptor cell type drug discovery effectiveness evaluation electronic cigarette use high throughput screening in vivo in vivo evaluation interpeduncular nucleus male member molecular dynamics new therapeutic target nicotine abuse nicotine cessation nicotine self-administration nicotine vapor novel novel therapeutic intervention pharmacologic receptor receptor function recruit scaffold sex small molecule success therapeutic development tool validation studies virtual virtual screening

项目摘要

Project Summary Tobacco addiction remains a leading cause of death and disease worldwide. Although many individuals express a desire to quit, available therapeutics have proven to be only moderately efficacious, with cessation success rates <25% after one year. In this proposal, we will explore the role of G protein-coupled receptor 3 (GPR3) in modulating nicotine reinforcement and aversion. GPR3 is a constitutively active orphan receptor that activates Gs leading to increased levels of cAMP within cells. GPR3 is highly expressed in the medial habenula, suggesting it may be a critical modulator of the habenulo-interpeduncular pathway that regulates nicotine aversion. Thus, GPR3 is a novel therapeutic target for nicotine cessation that should be investigated both pharmacologically and mechanistically. However, in vivo studies of GPR3 are restricted due to the limited availability of small molecule ligands for this receptor. The goal of this project is to discover, validate and develop GPR3 agonists for in vivo studies related to nicotine abuse. This will be accomplished by conducting high- throughput virtual screens of millions of compounds from commercial space followed by confirmatory screens in a functional assay. We will then conduct structure activity relationship campaigns on hit scaffolds to determine the potency, efficacy, and selectivity of potential GPR3 agonists as well as initial ADME/PK profiles. We hypothesize that optimized probes of GPR3 will decrease self-administration of nicotine by increasing aversive effects through stimulation of the MHb-IPN pathway. We will test the in vivo efficacy of lead GPR3 probes in altering intravenous nicotine self-administration at various nicotine doses. In addition, we will characterize GPR3 expression patterns in a brain region and cell type specific manner. Upon completion of this grant, we expect to have a potent, selective GPR3 agonist probe validated in both cell-based functional assays, and behavioral models of nicotine abuse. Novel GPR3 agonists developed under this application will serve as tools to investigate the signaling mechanisms and in vivo functions of GPR3 within the context of health and disease.

项目摘要烟草成瘾仍然是全球死亡和疾病的主要原因。尽管许多人表达事实证明，戒烟的愿望仅是中等效率的，并停止成功一年后比率<25％。在此提案中，我们将探讨G蛋白偶联受体3（GPR3）在调节尼古丁的增强和厌恶。 GPR3是一种激活的组成型活性孤儿受体 g s导致细胞内cAMP的水平增加。 GPR3在内侧Habenula中高度表达，表明它可能是调节尼古丁的Habenulo-Terteruncular途径的关键调节剂厌恶。这是GPR3是尼古丁停止的新型热目标，应研究两者在药理和机械上。但是，由于极限，GPR3的体内研究受到限制该接收器的小分子配体的可用性。该项目的目的是发现，验证和发展与尼古丁滥用有关的体内研究的GPR3激动剂。这将通过进行高商业空间中数百万种化合物的吞吐量虚拟屏幕，然后是确认屏幕功能测定。然后，我们将对脚手架进行结构活动关系活动，以确定潜在的GPR3激动剂以及初始ADME/PK轮廓的效力，效率和选择性。我们假设GPR3的优化问题将通过增加厌恶性来减少尼古丁的自我管理通过刺激MHB-IPN途径的影响。我们将测试铅GPR3问题的体内效率在各种尼古丁剂量下改变静脉注射尼古丁自我给药。此外，我们将描述GPR3 大脑区域和细胞类型特异性方式的表达模式。完成这笔赠款后，我们希望具有在两个基于细胞的功能测定中验证的潜力，选择性的GPR3激动剂探针和行为尼古丁滥用模型。在此应用中开发的新型GPR3激动剂将作为调查的工具在健康和疾病的背景下，GPR3的信号传导机制和体内功能。