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多巴胺受体的负变构调节剂作为治疗先导 药物使用障碍 摘要：多巴胺受体（DR）在细胞信号传导过程中起着关键作用， 调节神经系统内的信息传递。DR包括五种不同的 亚型细分为两个家族，D1样（D1 R和D5 R）和D2样（D2 R，D3 R， 和D4 R），产生深刻多样的生理效应。特别是，D3 R 拮抗剂已经被研究作为治疗物质使用的治疗方法 药物依赖性精神障碍（SUD），无论是在破坏药物寻求动机和预防复发。 在过去十年中，药物过量死亡人数增加了一倍多，主要是由于 阿片类药物滥用，强调迫切需要确定新的SUD疗法， 对阿片类药物SUD有效。最近的证据表明，D3 R拮抗作用可能是一种 对阿片类药物SUD的有效治疗。然而，高序列同源性 D3 R和其他GPCR在其正构结合位点内共享的这种结构使得 发现高选择性化合物困难，导致潜在的脱靶侧 由于这些试剂同时调节受体而产生的效应。现在， 除了高度保守的正构位点，许多G蛋白偶联受体， 包括DR，具有不同的和非保守的变构位点。因此， 通过与变构位点的相互作用调节受体， 非常有选择性。在这里，我们寻求开发结构新颖的D3 R负变构 作为新的化学探针具有特殊的D3 R选择性的调节剂， 治疗先导，总体目标是支持D3 R拮抗剂的开发 SUD疗法。为了发现D3 R的高选择性变构拮抗剂， 我们采用NIH小分子文库的高通量筛选。图书馆是 使用D3 R介导的β-抑制蛋白募集测定进行初步筛选。对手命中率 使用正构配体对放射性配体置换进行反筛选， 鉴定出三种具有变构特性的有前景的命中化合物。在这 研究，我们将开发灵活，强大的合成路线，以每一个支架，以促进 药物化学将评估三种支架的类似物的效力，D3 R 选择性和初步的体外药代动力学性质，以确定最 有前途的系列，以推进迭代药物化学优化。最 有前途的系列将进一步优化，重点是必要的属性， 体内探针化合物。将对探针的D3 R选择性进行深入表征 在几种功能输出中，包括β-抑制蛋白募集和G蛋白激活。 Schild型功能测定将用于确认该化合物在非免疫应答中起作用。 在D3 R的竞争力。最后，体内药代动力学实验将提供 化合物给药指南。探针化合物将用于研究 D3 R变构位点的药理学，D3 R拮抗剂的治疗潜力， 为SUD提供新的治疗线索。