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

基本信息

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
项目类别：
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

项目摘要

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 2530万美国人每天遭受疼痛，另外2340万美国人报告了重大疼痛。全世界大约有五分之一的成年人中有1人患有疼痛，另外十分之一的成年人被诊断出患有慢性每年疼痛。我们旨在开发双重抑制剂，即同时抑制两个的单个小分子酶：可溶性环氧水解酶（SEH）和脂肪酸酰胺水解酶（FAAH）。最原始的这些化合物的机械上不同方面是它们同时抑制两种不同酶的能力那在疼痛和炎症中起着重要作用。此处描述的双SEH/FAAH抑制剂具有潜力用作疼痛管理中一种有前途的新型非阿片类药物治疗策略。在我们以前的NIH SC2中格兰特（GM135020），我们确定了几种非常有效的双抑制剂，其中一种在急性大鼠模型中进行了测试炎症性疼痛。证明该双重抑制剂的抗伤害感受提供了第一个证据，表明双重 SEH/FAAH抑制剂减轻了稀释的福尔马林注射引起的急性炎症性疼痛。我们还观察到，这种双重抑制剂比传统的非甾体固醇产生抗伤害感受抗炎药酮。在拟议的研究中，我们将合成并评估新的文库旨在与两个靶酶同时相互作用的配体，评估和改善药物样这些分子的特性，并评估两个先前鉴定的双重抑制剂是否与新化合物（在此提案中确定）可减轻鼠的体内慢性炎症性疼痛的疼痛慢性炎症疼痛的模型。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起点疼痛管理研究。因为该课程与现有镇痛药具有不同的生物学靶标是解决与现有阿片类药物和非现有问题有关的长期存在问题的机会疼痛管理中的阿片类药物疗法。据我们所知，该提议是第一次尝试使用的策略双重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，合成和体内工具是严格，全面的，并且创新的。这个多收益计划是我们双重抑制生成/优化程序中的一个专业。我们的研究可以为未来研究在镇痛中使用双重配体策略的好处提供基础。该提案代表了加利福尼亚州的两个西班牙裔服务机构之间的合作工作大学，富勒顿和加利福尼亚州立大学，东湾，与加利福尼亚大学戴维斯大学。我们的多学科团队拥有解决该项目的专业知识和资源地平线以确保持续成功。