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.

该项目的目标是开发和测试relaxin-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性、慢性复发性的 紊乱。目前的疗法还不够，因此需要基于新靶点的新药物。 最近脱孤的relaxin-3/RXFP3系统包含内源性神经肽relaxin-3及其 同源 G 蛋白偶联受体 RXFP3。多种证据表明 RXFP3 拮抗作用是 治疗酒精成瘾和复发的新疗法目标。尽管 RXFP3 拮抗肽 可用，但对非肽小分子拮抗剂的需求尚未得到满足，这些拮抗剂是系统性的 具有生物利用度并且可以穿透血脑屏障，进一步验证relaxin-3/RXFP3系统作为 新的药物靶点。迄今为止，我们小组在这方面已经取得了重大进展。我们已经开发出稳定的 基于 RXFP3 细胞的 cAMP 高通量筛选测定并完成筛选活动以鉴定 对手击中。对热门化合物的重点结构-活性关系研究取得了第一个成果 系列小分子拮抗剂，Ke <500 nM，对 RXFP3 的选择性高于其他拮抗剂 受体亚型RXFP1，可以渗透到大脑中。在此应用中，我们建议进一步完善我们的 早期的先导化合物通过三个迭代特异性产生用于体内研究的拮抗剂探针 目标。在目标 1 中，我们将优化 RXFP3 拮抗剂的效力、受体选择性和药物样特性 使用药物化学。在目标 2 中，我们将使用 RXFP3 功能性 cAMP 测定来表征化合物 和放射性配体结合测定。将评估选定化合物对 RXFP1 的受体选择性 和 RXFP4（松弛素家族的两种亚型），并在目标分析筛选中进一步评估。有效且 然后将使用一系列 ADME 和药代动力学测定来表征选择性化合物。瞄准 3、我们将在酒精强化动物模型中测试目标 1 和 2 中开发的最佳化合物 压力引起的恢复。总体而言，该项目的完成将为以下领域提供体内拮抗剂探针： 药理学验证relaxin-3/RXFP3系统作为治疗酒精中毒的新靶点。

项目成果

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

Relaxin-3/RXFP3 系统的第一个非肽拮抗剂的发现和表征。

• 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