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.

项目概要尽管许多人表示，烟草成瘾仍然是世界范围内死亡和疾病的主要原因。想要戒烟，现有的治疗方法已被证明只有中等效果，戒烟成功一年后比率<25% 在本提案中，我们将探讨 G 蛋白偶联受体 3 (GPR3) 在其中的作用。 GPR3 是一种组成型活性孤儿受体，可激活尼古丁强化和厌恶。 Gs 导致细胞内 cAMP 水平增加，GPR3 在内侧缰核中高度表达，表明它可能是调节尼古丁的缰核-脚间途径的关键调节剂因此，GPR3 是戒烟的新治疗靶点，应该同时进行研究。然而，GPR3的体内研究由于有限而受到限制。该项目的目标是发现、验证和开发该受体的小分子配体。 GPR3 激动剂用于与尼古丁滥用相关的体内研究这将通过进行高强度研究来完成。对来自商业空间的数百万种化合物进行吞吐量虚拟筛选，然后在然后，我们将在命中支架上进行结构活性关系活动以确定潜在 GPR3 激动剂的效力、功效和选择性以及初始 ADME/PK 概况。促进 GPR3 的优化探针将通过增加厌恶感来减少尼古丁的自我施用我们将测试先导 GPR3 探针的体内功效。改变不同尼古丁剂量的静脉尼古丁自我给药此外，我们将表征 GPR3。在完成这项资助后，我们期望以大脑区域和细胞类型特定的方式表达模式。拥有在基于细胞的功能分析和行为分析中得到验证的有效、选择性 GPR3 激动剂探针在此应用下开发的新型 GPR3 激动剂模型将作为研究工具。 GPR3 在健康和疾病背景下的信号传导机制和体内功能。