Optimization of MrgX1 allosteric agonists as potential therapies for chronic pain

MrgX1 变构激动剂的优化作为慢性疼痛的潜在疗法

• 批准号: 9903279
• 负责人: Corey R. Hopkins
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903279
• 关键词: Adverse effects; Affective; Afferent Neurons; Agonist; Analgesics; Back; Binding; Binding Proteins; Biological Assay; Brain; Caliber; Cellular Assay; Characteristics; Clinical; Data; Development; Dose; Dose-Limiting; Drug Kinetics; Equilibrium; Family; Funding; Future; G-Protein-Coupled Receptors; Goals; Grant; Health; Homologous Gene; Human; In Vitro; Intervention; Lead; Ligation; Measures; Medicine; Modeling; Mus; Neuraxis; Neurons; Nociceptors; Opioid; Oral; Orphan; Pain; Pathway interactions; Penetration; Permeability; Persistent pain; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Plasma Proteins; Play; Positioning Attribute; Property; Research; Risk; Role; Signal Transduction; Skin; Solubility; Spinal Ganglia; Spinal nerve structure; Testing; Toxicology; Viscera; Work; addiction; analog; chemical synthesis; chronic constriction injury; chronic pain; conditioned place preference; design; experience; health economics; improved; in vivo; in vivo evaluation; lead optimization; meetings; member; mouse model; novel; pain model; pharmacokinetics and pharmacodynamics; pre-clinical; programs; receptor; scaffold; side effect; spontaneous pain; tool; transmission process

Chronic pain is a major health and economic problem worldwide. Because the major analgesics (e.g., opioids) bind to receptors that are widely expressed throughout the central nervous system (CNS), dose-limiting adverse effects and significant risk of addiction and abuse present substantial barriers to their clinical use. Pain sensing neurons (a.k.a nociceptors) in dorsal root ganglion (DRG) play essential role in pain transmission by detecting painful signals in the periphery such as skin and viscera. Therefore, targeting molecules specifically expressed in nociceptors may offer an opportunity for pain-selective pharmacologic interventions. Our previous data have shown that Mrgs including mouse MrgC11 and human MrgX1 are specifically expressed in nociceptors in DRG and constitute an endogenous anti-pain pathway. Funded R03 grant allowed us to identify selective and potent MrgX1 allosteric agonists. Preliminary data showed that two allosteric agonists inhibited persistent pain in humanized MrgX1 mice. MrgX1 allosteric agonists may potentially become novel anti-chronic pain drugs with limited CNS-related side effects. In this proposal, we will improve and optimize MrgX1 allosteric agonists and test their analgesic efficacy in mice. Highly selective agonists, and for the purpose of this proposal, allosteric agonists, are needed in order to better understand the respective role of MrgX1 in these studies of chronic pain. We have recently discovered a novel class of allosteric agonists with potency on MrgX1 and selectivity against MrgX2. These selective allosteric agonists offer a unique opportunity to test the hypothesis presented in this proposal. In order to develop first-in-class, potent, selective and CNS penetrant MrgX1 allosteric agonists, we will optimize our lead scaffold such that the tool compound will possess the appropriate properties, a balance of potency, selectivity and DMPK. We will utilize an iterative medicinal chemistry approach which will enable all of the attributes to be evaluated in parallel. Once the tool compound(s) have been determined, we will then test these compounds in the humanized MrgX1 mouse model.

慢性疼痛是全球一个重大的健康和经济问题。因为主要的镇痛药（例如阿片类药物） 结合在整个中枢神经系统（CNS），剂量限制的受体中结合 不良影响和成瘾和虐待的重大风险呈现出其临床使用的重大障碍。疼痛 在背根神经节（DRG）中感应神经元（又名伤害感受器）在疼痛传播中起着至关重要的作用 检测外围的疼痛信号，例如皮肤和内脏。因此，专门针对分子 在伤害感受器中表达的可能会为疼痛选择性药物干预提供机会。我们的先前 数据表明，包括小鼠MRGC11和人MRGX1在内的MRG在 DRG中的伤害感受器，构成了内源性抗PAIN途径。资助的R03赠款使我们能够确定 选择性和有效的MRGX1变构激动剂。初步数据表明，两种变构激动剂抑制了 人性化MRGX1小鼠的持续疼痛。 MRGX1变构激动剂可能会成为新颖的抗童态 与CNS相关的副作用有限的疼痛药物。在此建议中，我们将改进和优化MRGX1变构 激动剂并在小鼠中测试其镇痛功效。高度选择性激动剂，目的 为了更好地了解MRGX1在这些中的各自作用，需要提出的变构激动剂 慢性疼痛的研究。我们最近发现了一种具有效力的新颖的变构激动剂类 MRGX1和针对MRGX2的选择性。这些选择性变构激动剂提供了一个独特的机会来测试 该提议中提出的假设。为了发展一流的，有效的，选择性和CNS渗透率 MRGX1变构激动剂，我们将优化我们的铅脚手架，以使工具化合物将拥有 适当的属性，效力，选择性和DMPK的平衡。我们将使用迭代药用 化学方法将使所有属性都可以并行评估。一旦工具 已经确定化合物，然后我们将在人源化的MRGX1小鼠中测试这些化合物 模型。