Small molecule antagonist probes for the relaxin-3/RXFP3 system

松弛素 3/RXFP3 系统的小分子拮抗剂探针

• 批准号: 10410553
• 负责人: JOYCE BESHEER
• 金额: $ 67.74万
• 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: 2020-09-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410553
• 关键词: Acute; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Anxiety; Arousal; Attenuated; Behavior; Behavioral; Binding; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Cell Line; Cells; Chinese Hamster Ovary Cell; Chronic; Clinical; Complement; Computer Analysis; Cues; Cyclic AMP; Data; Development; Disease; Dose; Drug Kinetics; Eating; Evaluation; Family; G-Protein-Coupled Receptors; Goals; Homology Modeling; In Vitro; Injections; Knockout Mice; Lead; Ligands; Link; Locomotion; Messenger RNA; Metabolic; Modification; Motor Activity; Naltrexone; Names; Neuropeptides; Patients; Peptides; Peripheral; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Plasma; Play; Property; Rattus; Relapse; Relaxin; Research; Role; Route; Self Administration; Series; Stress; Structure-Activity Relationship; Sucrose; System; Testing; Therapeutic; Therapeutic Agents; acamprosate; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol preferring rats; alcohol reinforcement; alcohol relapse; alcohol seeking behavior; alcohol testing; alcohol use disorder; alcoholism therapy; analog; antagonist; base; behavioral phenotyping; behavioral study; biological adaptation to stress; design; hazardous drinking; high throughput screening; in silico; in vivo; inhibitor; intraperitoneal; medication compliance; new therapeutic target; novel; novel therapeutics; pharmacophore; preference; prevent; problem drinker; procedural memory; radioligand; receptor; scaffold; screening; side effect; small molecule; stress reduction; tool

The goal of this project is to develop and test small-molecule antagonist probes of the relaxin-3/RXFP3 system for behavioral studies in alcohol addiction and relapse. Alcohol addiction is a heterogeneous, chronic relapsing disorder. Current therapies are inadequate, and therefore new medications based on novel targets are needed. The recently deorphanized relaxin-3/RXFP3 system comprises the endogenous neuropeptide relaxin-3 and its cognate G protein-coupled receptor RXFP3. Multiple lines of evidence suggest that RXFP3 antagonism is a novel target for therapeutics to treat alcohol addiction and relapse. Although RXFP3 antagonist peptides are available, there are unmet needs for non-peptide small-molecule antagonists, which are systemically bioavailable and can penetrate the blood-brain barrier, to further validate the relaxin-3/RXFP3 system as a novel drug target. To date, our group has made significant progress in this regard. We have developed a stable RXFP3 cell-based cAMP high-throughput screening assay and completed a screening campaign to identify antagonist hits. Focused structure-activity relationship studies of the hit compound have resulted in the first series of small-molecule antagonists that have Ke <500 nM and are highly selective for RXFP3 over another receptor subtype RXFP1 and can penetrate into the brain. In this application, we propose to further refine our early lead-like compounds to produce antagonist probes for in vivo studies through three iterative specific aims. In Aim 1, we will optimize potency, receptor selectivity, and drug-like properties of RXFP3 antagonists using medicinal chemistry. In Aim 2, we will characterize compounds using an RXFP3 functional cAMP assay and a radioligand binding assay. Select compounds will be assessed for receptor selectivity against RXFP1 and RXFP4, two subtypes of the relaxin family, and further evaluated in a target profiling screen. Potent and selective compounds will then be characterized using a battery of ADME and pharmacokinetic assays. In Aim 3, we will test the best compounds, developed in Aims 1 and 2, in animal models of alcohol reinforcement and stress-induced reinstatement. Overall, completion of this project will provide in vivo antagonist probes to pharmacologically validate the relaxin-3/RXFP3 system as a novel target for treatment of alcoholism.

该项目的目的是开发和测试selaxin-3/rxfp3系统的小分子拮抗剂探针 用于酒精成瘾和复发的行为研究。酒精成瘾是一种异质，慢性复发 紊乱。当前的疗法不足，因此需要基于新靶标的新药物。 最近去脱磷素-3/rxfp3系统包括内源性神经肽lesearin-3及其ITS ITS 同源G蛋白偶联受体RXFP3。多种证据表明rxfp3拮抗是一种 治疗酒精成瘾和复发的治疗剂的新目标。虽然rxfp3拮抗剂肽是 可用，对非肽小分子拮抗剂有未满足的需求，这些拮抗剂是系统的 可生物利用并可以穿透血脑屏障，以进一步验证seliefin-3/rxfp3系统 新型药物靶标。迄今为止，我们的小组在这方面取得了重大进展。我们已经开发了一个稳定的 基于RXFP3单元的CAMP高通量筛查测定法，并完成了筛选活动以识别 对手命中。热门化合物的集中结构 - 活性关系研究导致了第一个 一系列的小分子拮抗剂，具有ke <500 nm并且对RXFP3高度选择性而不是另一个拮抗剂 受体亚型RXFP1可以渗透到大脑中。在此应用程序中，我们建议进一步完善我们的 早期的铅样化合物通过三个迭代特异性产生体内研究的拮抗剂探针 目标。在AIM 1中，我们将优化rxfp3拮抗剂的效力，受体选择性和类似药物的特性 使用药物化学。在AIM 2中，我们将使用RXFP3功能cAMP分析来表征化合物 和放射性结合测定法。将评估针对RXFP1的受体选择性的选择化合物 和RXFP4，是放松蛋白家族的两个亚型，并在目标分析屏幕中进一步评估。有效和 然后，选择性化合物将使用一系列ADME和药代动力学测定法进行表征。目标 3，我们将在Aims 1和2中开发的最佳化合物，在酒精加强的动物模型和 应力引起的恢复。总体而言，该项目的完成将为体内拮抗剂探针提供 药理学在药理学上验证了雷sin-3/rxfp3系统是酗酒治疗的新目标。

项目成果

Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System.

• DOI: 10.1021/acs.jmedchem.2c00508
• 发表时间: 2022-06-09
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Gay, Elaine A.;Guan, Dongliang;Van Voorhies, Kalynn;Vasukuttan, Vineetha;Mathews, Kelly M.;Besheer, Joyce;Jin, Chunyang
• 通讯作者: Jin, Chunyang