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

设计多种配体作为非阿片类镇痛药，用于治疗慢性疼痛

• 批准号: 10621646
• 负责人: Stevan Pecic
• 金额: $ 15.46万
• 依托单位: CALIFORNIA STATE UNIVERSITY FULLERTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621646
• 关键词: Absence of pain sensation; Acute Pain; Acute inflammatory pain; Adult; Adverse effects; American; Analgesics; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Behavioral; Biological; Biological Assay; Biomedical Research; California; Chronic inflammatory pain; Clinical Research; Computer Assisted; Coupled; Data; Development; Diagnosis; Dose; Drug Design; Drug Interactions; Drug Kinetics; Ensure; Enzymes; Epoxide hydrolase; Evaluation; FAAH inhibitor; Formalin; Foundations; Funding; Future; Generations; Goals; Grant; Health Professional; Hispanic-serving Institution; Hydrolase; Hypersensitivity; In Vitro; Inflammation; Injections; Investigation; Ketoprofen; Laboratories; Lead; Libraries; Ligands; Link; Liver Microsomes; Mechanics; Medical; Metabolic; Modeling; Modification; Molecular; Non-Steroidal Anti-Inflammatory Agents; Opioid; Opioid agonist; Pain; Pain management; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Physical Dependence; Play; Property; Protocols documentation; Rattus; Reporting; Research; Resources; Role; Structure; Structure-Activity Relationship; Testing; Therapeutic; United States National Institutes of Health; Universities; Work; addiction; analog; antinociception; behavior test; behavioral pharmacology; benzothiazole; chronic pain; chronic pain management; daily pain; design; disability; drug development; drug discovery; fatty acid amide hydrolase; improved; in silico; in vivo; inhibitor; innovation; intraperitoneal; multidisciplinary; new therapeutic target; non-opioid analgesic; novel; pain relief; pharmacophore; pre-clinical; preclinical development; programs; side effect; small molecule; success; tool; underrepresented minority student

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.

项目总结/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， 25.3 100万美国人每天遭受疼痛，另有2340万美国人报告严重疼痛。 全世界大约五分之一的成年人患有疼痛，另外十分之一的成年人被诊断为慢性疼痛。 每年的疼痛我们的目标是开发双重抑制剂，单一的小分子，将同时抑制两个 酶：可溶性环氧化物水解酶（sEH）和脂肪酸酰胺水解酶（FAAH）。最原始的， 这些化合物在机理上不同的方面是它们同时抑制两种不同酶的能力 在疼痛和炎症中起着重要作用。本文描述的双重sEH/FAAH抑制剂具有潜在的 作为一种有前途的新型非阿片类药物治疗策略用于疼痛管理。在我们之前的NIH SC2中， 格兰特（GM 135020），我们确定了几个非常有效的双重抑制剂，并在大鼠模型中进行了测试，急性 炎性疼痛。证明这种双重抑制剂的抗伤害性提供了双重抑制剂的第一个证据， sEH/FAAH抑制剂减轻足底注射稀释福尔马林引起的急性炎性疼痛。我们 还观察到这种双重抑制剂产生的抗伤害感受的剂量低于传统的非甾体类 抗炎药酮洛芬。在拟议的研究中，我们将合成和评估新的图书馆， 设计为同时与两种靶酶相互作用的配体，评估和改善药物样活性， 这些分子的性质，并评估是否有两个先前确定的双重抑制剂与 新的化合物（在该提议中鉴定）在大鼠体内产生针对慢性炎性疼痛的疼痛缓解 慢性炎性疼痛模型。 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。由于这类药物与现有的镇痛药具有不同的生物学靶点， 这是一个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。 阿片类药物治疗疼痛据我们所知，这一建议是第一次尝试使用 双重sEH/FAAH抑制剂作为疼痛管理的合理治疗策略。此外，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的，全面的， 新颖啊这种多管齐下的计划是我们的双重抑制生成/优化程序的强项。我们的研究 可能为将来研究使用双配体策略镇痛的益处提供基础。 这项提案代表了两个为西班牙裔服务的机构，加州州立大学 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该项目的专业知识和资源 以确保持续的成功。