Negative allosteric modulators of the D3 dopamine receptor as therapeutic leads for substance use disorders

D3 多巴胺受体的负变构调节剂作为药物滥用障碍的治疗先导药物

• 批准号: 10411908
• 负责人: Kevin J. Frankowski
• 金额: $ 19.44万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411908
• 关键词: Address; Agonist; Allosteric Site; Animal Model; Animals; Area; Basic Science; Binding; Binding Sites; Biological Assay; Cell Signaling Process; Chemicals; Chimera organism; Clinical Sciences; Cocaine; DRD2 gene; Development; Dopamine Antagonists; Dopamine Receptor; Dose; Drug Kinetics; Effectiveness; Evaluation; Exhibits; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Goals; Heroin; In Vitro; Incidence; Lead; Libraries; Ligand Binding; Ligands; Liver Microsomes; Mediating; Metabolic; Methamphetamine; Methods; Modification; Motivation; Mutagenesis; Nervous system structure; Nicotine; Opioid; Output; Pathology; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology Study; Physiological; Play; Property; Relapse; Research; Rewards; Risk; Role; Route; Sequence Homology; Series; Site; Structure-Activity Relationship; Substance Use Disorder; Surveys; System; Testing; Therapeutic; Translating; United States National Institutes of Health; analog; antagonist; beta-arrestin; dopamine D3 receptor; drug seeking behavior; effective therapy; experimental study; flexibility; functional group; high throughput screening; improved; in vivo; mood regulation; novel; novel therapeutics; opioid abuse; overdose death; pleasure; pre-clinical; pressure; prevent; protein activation; radioligand; receptor; recruit; scaffold; side effect; small molecule; small molecule libraries; tool; trend

Title: Negative allosteric modulators of the D3 dopamine receptor as therapeutic leads for substance use disorders Summary: Dopamine receptors (DRs) play a critical role in cell signaling processes and modulation of information transfer within the nervous system. DRs comprise five distinct subtypes subdivided into two families, D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R), that produce profoundly diverse physiological effects. In particular, D3R antagonists have been investigated as a therapeutic approach to treating substance use disorders (SUDs), both in disrupting drug seeking motivation and preventing relapse. Drug overdose deaths have more than doubled in the past decade driven largely by rising opioid abuse, underscoring the urgent need to identify new SUD therapies that are effective for opioid SUD. Recent evidence suggests that D3R antagonism may be an especially effective treatment for opioid SUD. However, the high sequence homology shared by the D3R and other GPCRs within their orthosteric binding sites has made the discovery of highly selective compounds difficult, leading to the potential for off-target side effects due to simultaneous receptor modulation by such agents. It is now appreciated that, in addition to highly conserved orthosteric sites, many G protein-coupled receptors, including DRs, possess distinct and non-conserved allosteric sites. Thus, compounds that modulate receptors through the interaction with an allosteric site have the potential to be profoundly selective. Here we seek to develop structurally novel D3R negative allosteric modulators that possess exceptional D3R selectivity as new chemical probes and therapeutic leads, in an overarching goal to support development of a D3R antagonist SUD therapy. In an effort to discover highly selective allosteric antagonists for the D3R, we employed a high-throughput screen of the NIH small molecule library. The library was initially screened using a D3R-mediated β-arrestin recruitment assay. Antagonist hits were counter-screened for radioligand displacement using an orthosteric ligand, which led to the identification of three promising hit compounds with allosteric properties. In this study, we will develop flexible, robust synthetic routes to each scaffold to facilitate medicinal chemistry. Analogs of the three scaffolds will be evaluated for potency, D3R selectivity and preliminary in vitro pharmacokinetic properties to identify the most promising series to advance for iterative medicinal chemistry optimization. The most promising series will be further optimized with an emphasis on the requisite properties for an in vivo probe compound. The probe will be intensively characterized for D3R selectivity in several functional outputs including β-arrestin recruitment and G-protein activation. Schild-type functional assays will be used to confirm that this compound acts in a non- competitive manner at the D3R. Finally, in vivo pharmacokinetic experiments will provide a guide for compound dosing. The probe compound will be used to study the pharmacology of D3R allosteric sites, the therapeutic potential of D3R antagonists and provide new therapeutic leads for SUDs.

标题：D3 多巴胺受体负变构调节剂作为治疗先导药物 对于物质使用障碍 摘要：多巴胺受体 (DR) 在细胞信号传导过程中发挥着关键作用， 神经系统内信息传递的调节包括五个不同的部分。 亚型细分为两个家族：D1 样（D1R 和 D5R）和 D2 样（D2R、D3R、 和 D4R），产生极其不同的生理效应。 拮抗剂已被研究作为治疗药物滥用的治疗方法 障碍（SUD），既可以扰乱寻求药物的动机，又可以防止复发。 过去十年，药物过量死亡人数增加了一倍多，这主要是由于药物过量死亡人数上升 阿片类药物滥用，强调迫切需要确定新的 SUD 疗法 最近的证据表明 D3R 拮抗作用可能是一种对阿片类药物 SUD 有效的药物。 对阿片类药物SUD特别有效，但序列同源性高。 D3R 和其他 GPCR 在其正构结合位点内共享，使得 发现高选择性化合物很困难，导致潜在的脱靶现象 现在人们认识到由于这些药物同时进行受体调节而产生的影响。 除了高度保守的正构位点之外，许多 G 蛋白偶联受体 包括 DR 在内的化合物具有独特且非保守的变构位点。 通过与变构位点相互作用调节受体有可能 在这里，我们寻求开发结构新颖的 D3R 负变构。 作为新的化学探针，调节剂具有出色的 D3R 选择性， 治疗先导，总体目标是支持 D3R 拮抗剂的开发 SUD 疗法致力于发现 D3R 的高选择性变构拮抗剂， 我们采用了 NIH 小分子库的高通量筛选。 最初使用 D3R 介导的 β-抑制蛋白招募试验进行筛选。 使用正构配体对放射性配体置换进行反筛选， 导致鉴定出三种具有变构特性的有前途的热门化合物。 研究中，我们将为每个支架开发灵活、稳健的合成路线，以促进 药物化学将评估三种支架的类似物的效力，D3R。 选择性和初步体外药代动力学特性，以确定最 有望推进迭代药物化学优化的系列。 系列将进一步优化，重点是必要的性能 该探针将针对 D3R 选择性进行深入表征。 多种功能输出，包括 β-arrestin 招募和 G 蛋白激活。 Schild 型功能测定将用于确认该化合物在非 最后，体内药代动力学实验将提供 D3R 的竞争方式。 化合物剂量指南将用于研究探针化合物。 D3R变构位点的药理学、D3R拮抗剂的治疗潜力和 为 SUD 提供新的治疗线索。