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.

慢性疼痛是世界范围内的主要健康和经济问题。因为主要的止痛药（例如，阿片类药物） 与在整个中枢神经系统（CNS）中广泛表达的受体结合，剂量限制性 副作用以及成瘾和滥用的显著风险对它们的临床使用构成了实质性障碍。疼痛 背根神经节（DRG）中的感觉神经元（也称为伤害感受器）通过以下方式在疼痛传递中起重要作用： 检测外周如皮肤和内脏的疼痛信号。因此，靶向分子特异性 在伤害感受器中的表达可能为疼痛选择性药物干预提供了机会。我们以前的 数据表明，包括小鼠MrgC11和人MrgX1在内的Mrgs特异性表达于 DRG中的伤害感受器，并构成内源性抗疼痛通路。R03资助使我们能够确定 选择性和有效的MrgX1变构激动剂。初步数据显示，两种别构激动剂抑制了 人源化MrgX1小鼠的持续疼痛。MrgX1变构激动剂可能成为新的抗慢性 具有有限CNS相关副作用的止痛药。在本研究中，我们将改进和优化MrgX1变构酶， 激动剂并在小鼠中测试它们的镇痛功效。高选择性激动剂，为了达到这个目的， 为了更好地理解MrgX1在这些疾病中的各自作用，需要使用变构激动剂。 慢性疼痛的研究。我们最近发现了一类新的变构激动剂， MrgX1和对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，以测试 这一建议中提出的假设。为了开发一流的、强效的、选择性的中枢神经系统渗透剂， MrgX1变构激动剂，我们将优化我们的先导支架，使得工具化合物将具有 合适的性质，效力、选择性和DMPK的平衡。我们将使用一种迭代的药物 化学方法，这将使所有的属性进行平行评价。一旦工具 已经确定了化合物，然后我们将在人源化MrgX1小鼠中测试这些化合物 模型