Optimization of MrgX1 allosteric agonists as potential therapies for chronic pain

慢性疼痛是全球范围内的一个主要健康和经济问题。因为主要的镇痛剂(如阿片类药物) 与广泛表达于中枢神经系统(CNS)的受体结合，剂量限制 不良反应和成瘾和滥用的巨大风险给它们的临床应用带来了很大的障碍。疼痛 背根神经节(DRG)的感觉神经元(又称伤害性感受器)通过以下途径在痛觉传递中发挥重要作用 检测周围的疼痛信号，如皮肤和内脏。因此，以分子为靶标 在伤害性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和人类MRGX1在内的MRG在 DRG中的伤害性感受器构成内源性止痛通路。受资助的R03拨款使我们能够确定 选择性和强效的MRgX1变构激动剂。初步数据显示，两种变构激动剂抑制了 人源化的mrgX1小鼠的持续性疼痛。MRGX1变构激动剂可能成为新的抗慢性药物 止痛药与中枢神经系统相关的副作用有限。在这个方案中，我们将改进和优化mrgX1变构 并在小鼠身上测试其止痛效果。高选择性的激动剂，为了这个目的 为了更好地理解MRGX1在这些过程中的各自作用，需要提出变构激动剂 对慢性疼痛的研究。我们最近发现了一类新的变构激动剂，其效力为 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来测试 本提案中提出的假设。为了开发一流的、高效的、选择性的、CNS渗透剂 我们将优化我们的铅支架，使工具化合物具有 适当的性质，在效力、选择性和DMPK之间取得平衡。我们将利用一种迭代的药物 化学方法，这将使所有的属性能够被并行评估。一旦该工具 化合物(S)已经确定，然后我们将在人源化的MRGX1小鼠身上测试这些化合物 模特。

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.