Designed Multiple Ligands as Non-opioid Analgesics for Treating Chronic Pain

项目摘要/摘要 慢性疼痛是全球残疾的主要原因。根据美国国立卫生研究院的数据，近 2530万美国人每天都在遭受疼痛，另有2340万美国人报告说有很大的疼痛。 全世界大约五分之一的成年人患有疼痛，另有十分之一的成年人被诊断为慢性 每年都会感到疼痛。我们的目标是开发双重抑制剂，单个小分子同时抑制两个 酶：可溶性环氧化物水解酶(SEH)和脂肪酸酰胺水解酶(FAAH)。最具原创性和 这些化合物在机理上的不同之处在于它们能够同时抑制两种不同的酶 在疼痛和炎症中起着重要作用。这里描述的双重sEH/FAAH抑制剂具有潜在的 有望作为一种有前景的新型非阿片类药物治疗策略用于疼痛治疗。在我们之前的NIH SC2中 Grant(GM135020)，我们发现了几种非常有效的双重抑制剂，其中一种在急性脑缺血大鼠模型上进行了测试。 炎症性疼痛。证明这种双重抑制剂的抗伤害性提供了第一个证据 SEH/FAAH抑制剂减轻足底注射稀福尔马林引起的急性炎症性疼痛。我们 还观察到，这种双重抑制剂在比传统的非类固醇药物更低的剂量下产生抗伤害作用 抗炎药酮洛芬。在拟议的研究中，我们将综合和评估 被设计为同时与两种靶酶相互作用的配体，评估和改进类药物 这些分子的性质，并评估之前发现的两种双重抑制剂与 新化合物(在本提案中确定)在大鼠体内对慢性炎症性疼痛产生缓解作用 慢性炎症性疼痛模型。 我们建议研究的化合物代表了一个急需的、完全新颖的非阿片类药物的起点 疼痛管理研究。因为这类药物与现有的止痛药具有不同的生物靶点，所以它 代表着解决与现有阿片类药物和非阿片类药物有关的长期问题的机会 疼痛管理中的阿片类药物治疗。据我们所知，这项建议是首次尝试使用 双sEH/FAAH抑制剂作为一种合理的疼痛控制治疗策略。此外，该设计 这些双重抑制剂背后的原理和合成和体内工具是严格、全面和 创新。这一多管齐下的计划是我们双重抑制生成/优化计划的强项。我们的研究 可能为未来研究双配体策略在镇痛中的益处提供基础。 这项提案代表了加州州立大学两个为拉美裔服务的机构之间的合作 大学、富勒顿大学和加州州立大学东湾分校，与 加州大学戴维斯分校。我们的多学科团队拥有解决这一项目的专业知识和资源 在地平线上，以确保继续成功。

Project Summary/Abstract Chronic pain is the primary cause of disability worldwide. According to the National Institutes of Health, nearly 25.3 million Americans suffer from daily pain, and another 23.4 million Americans report significant pain. Approximately 1 in 5 adults worldwide suffer from pain, and another 1 in 10 adults are diagnosed with chronic pain each year. We aim to develop dual inhibitors, single small molecules that will simultaneously inhibit two enzymes: soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH). The most original and mechanistically distinct aspect of these compounds is their ability to simultaneously inhibit two different enzymes that play significant roles in pain and inflammation. Dual sEH/FAAH inhibitors described here have the potential to be used as a promising novel non-opioid therapeutic strategy in pain management. In our previous NIH SC2 grant (GM135020), we identified several very potent dual inhibitors, and one was tested in a rat model of acute inflammatory pain. Demonstrating antinociception of this dual inhibitor provided the first evidence that a dual sEH/FAAH inhibitor alleviates acute inflammatory pain induced by intraplantar injection of dilute formalin. We also observed that this dual inhibitor produces antinociception at lower doses than the traditional nonsteroidal anti-inflammatory drug ketoprofen. In the proposed studies, we will synthesize and evaluate novel libraries of ligands that are designed to interact simultaneously with both target enzymes, assess and improve the drug-like properties of these molecules, and evaluate whether two previously identified dual inhibitors together with the new compounds (identified in this proposal) produce pain relief against chronic inflammatory pain in vivo in a rat model of chronic inflammatory pain. The compounds we propose to study represent a much-needed, completely novel non-opioid starting point in pain management research. Because this class has different biological targets from existing analgesics, it represents an opportunity to solve long-standing problems that have been linked to the existing opioid and non- opioid therapies in pain management. To our knowledge, this proposal is the first attempt to use the strategy of dual sEH/FAAH inhibitors as a rational therapeutic strategy for pain management. In addition, the design principles and synthetic and in vivo tools behind these dual inhibitors are rigorous, comprehensive, and innovative. This multipronged plan is a forte in our dual inhibition generation/optimization program. Our studies may provide a foundation for the future investigation of the benefits of using the dual ligand strategy in analgesia. This proposal represents a collaborative work between two Hispanic-serving institutions, California State University, Fullerton and California State University, East Bay, with a strong collaborative partnership with the University of California, Davis. Our multidisciplinary team has the expertise and resources to tackle this project on the horizon to ensure continued success.