Discovery and development of GPR3 agonists for nicotine cessation

发现和开发用于戒烟的 GPR3 激动剂

• 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
• 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

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 烟草成瘾仍然是世界范围内导致死亡和疾病的主要原因。尽管许多人表示 戒烟的愿望，现有的治疗方法已被证明只是适度有效，戒烟成功。 一年后利率为25%。在这项研究中，我们将探讨G蛋白偶联受体3(GPR3)在 调节尼古丁的强化和厌恶。GPR3是一种结构性活性孤儿受体，它能激活 G-S导致细胞内cAMP水平升高。GPR3在内侧缰核高度表达， 提示它可能是调节尼古丁的缰核-脚间通路的关键调节器。 厌恶。因此，GPR3是尼古丁戒断的一个新的治疗靶点，应该同时进行研究 从药理上和机械上来说。然而，GPR3的体内研究由于受到限制而受到限制 该受体的小分子配体的可用性。该项目的目标是发现、验证和开发 GPR3激动剂，用于与尼古丁滥用有关的体内研究。实现这一目标的途径是进行高效率的 来自商业空间的数百万种化合物的吞吐量虚拟屏幕，随后是 一种实用的分析。然后，我们将在命中的脚手架上进行结构活动关系活动，以确定 潜在的GPR3激动剂的效力、疗效和选择性以及最初的ADME/PK谱。我们 假设优化的GPR3探针将通过增加厌恶程度来减少尼古丁的自我给药 通过刺激MHB-IPN途径发挥作用。我们将测试铅GPR3探针在体内的效果 改变不同尼古丁剂量的静脉注射尼古丁自我给药。此外，我们还将描述GPR3 大脑区域的表达模式和细胞类型的特定方式。完成这笔拨款后，我们预计 有一个有效的，选择性的GPR3激动剂探针，在基于细胞的功能分析和行为学分析中都得到了验证 尼古丁滥用的典范。在此应用下开发的新型GPR3激动剂将作为研究工具 GPR3在健康和疾病背景下的信号机制和体内功能。