Developing multitarget enzyme inhibitors as safe and effective anti-migraine treatments

开发多靶点酶抑制剂作为安全有效的抗偏头痛治疗方法

• 批准号: 10714658
• 负责人: Ram Kandasamy
• 金额: $ 11.9万
• 依托单位: CALIFORNIA STATE UNIVERSITY HAYWARD
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714658
• 关键词: Acids; Acute inflammatory pain; Adverse effects; Analgesic Overuse Headaches; Analgesics; Anatomy; Anti-Inflammatory Agents; Behavior; Behavioral; Binding; Biological; Biological Assay; Body Regions; Brain; Cannabinoids; Chemicals; Clinical Pharmacology; Data; Development; Dose; Drug Design; Drug Interactions; Dura Mater; Endocannabinoids; Ensure; Enzyme Inhibitor Drugs; Enzymes; Epoxide hydrolase; Evaluation; FAAH inhibitor; Female; Foundations; Future; Gastric ulcer; Goals; Headache; Hispanic-serving Institution; Human; Hydrolase; Hyperalgesia; Hypersensitivity; In Vitro; Inflammation; Inflammatory; Investigation; Ketoprofen; Lead; Libraries; Ligands; Link; Liver Microsomes; Location; Mental Depression; Mentorship; Metabolic; Metabolic Pathway; Migraine; Modeling; Nausea; Nitroglycerin; Non-Steroidal Anti-Inflammatory Agents; Opioid; Pain; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Prevalence; Property; Rattus; Recurrence; Resources; Rewards; Rodent; Rodent Model; Role; Running; Serotonin Agonists; Structure-Activity Relationship; Sumatriptan; Symptoms; System; Techniques; Testing; Tetrahydrocannabinol; Therapeutic; Unilateral Headaches; Universities; Validation; Vomiting; Washington; Work; addiction; allodynia; analog; anandamide; antinociception; behavior test; behavioral pharmacology; benzothiazole; clinical center; design; drug discovery; exogenous cannabinoid; fatty acid amide hydrolase; functional restoration; improved; in vivo; in vivo evaluation; inflammatory pain; inhibitor; innovation; male; medical schools; migraine treatment; multidisciplinary; nervous system disorder; non-opioid analgesic; novel; pain model; pain relief; pharmacologic; pre-clinical; prevent; response; sedative; side effect; single molecule; small molecule; success; synergism; targeted agent; triptans; undergraduate student

PROJECT SUMMARY/ABSTRACT Migraine is the most common neurological disorder in the world characterized by episodes of severe headache accompanied by a variety of symptoms such as nausea, vomiting, and depression of activity. Despite its prevalence, treatments for migraine are poor. Nonspecific analgesics such as opioids and nonsteroidal anti- inflammatory drugs (NSAIDs) produce pain relief, but repeated may produce addiction and gastric ulcers, respectively. Traditional treatments for migraine such as triptans (serotonin receptor agonists) are plagued by side effects, while repeated use of certain anti-migraine treatments worsen headache in a condition known as medication-overuse headache (MOH). Thus, there is a desperate need for new non-opioid anti-migraine agents with novel mechanisms of action. To this end, we aim to develop dual inhibitors, single small molecules that will simultaneously inhibit two pain-related 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 inhibit two different enzymes that play significant roles in pain and inflammation within the trigeminovascular system simultaneously. Dual sEH/FAAH inhibitors described here have the potential to be used as a promising novel non-opioid anti-migraine strategy. Our undergraduate students have identified several very potent dual inhibitors and tested our lead inhibitor in vivo to demonstrate antinociception in a rat model of acute inflammatory pain. We also observed that this dual inhibitor produces antinociception at lower doses than traditional NSAID ketoprofen and does not produce behaviorally disruptive side effects. In the proposed studies we will rigorously evaluate our two lead dual inhibitors in a rat model of migraine pain, synthesize and evaluate novel libraries of ligands that are designed to interact simultaneously with both target enzymes, assess the anti-migraine effects of these new ligands, and evaluate whether administration of our dual inhibitors produce opioid-like rewarding effects or medication overuse headache. The compounds we propose to study represent a completely novel non-opioid, groundbreaking effort in anti-migraine treatments. Because this class has different biological targets from existing treatments, it represents an opportunity to solve long-standing problems that have been linked to the existing anti-migraine therapies (e.g., opioids, triptans). To our knowledge, this proposal is the first attempt to use the strategy of dual sEH/FAAH inhibitors as a rational anti-migraine therapeutic strategy. In addition, the design principles, synthetic and in vivo strategies behind these dual inhibitors are truly multi-disciplinary, rigorous, comprehensive, and innovative. Our studies will provide a firm foundation for the future investigation of using this dual ligand strategy as a treatment for migraine pain. This proposal represents collaborative work between two Hispanic-serving institutions, Cal State East Bay and Cal State Fullerton, with mentorship from the Center for Clinical Pharmacology at Washington University School of Medicine in St. Louis. Our multidisciplinary team has expertise and resources to tackle this project on the horizon to ensure continued success.

项目摘要/摘要 偏头痛是世界上最常见的神经系统疾病，其特征是严重头痛的发作 伴随着各种症状，例如恶心，呕吐和活动抑郁。尽管有它 患病率，偏头痛治疗差。非特异性镇痛药，例如阿片类药物和非甾体类抗 炎症药（NSAIDS）可减轻疼痛，但重复会产生成瘾和胃溃疡， 分别。偏头痛的传统治疗方法，例如triptans（5-羟色胺受体激动剂）。 副作用，而在某些抗偏ra骨治疗的重复使用时，头痛使头痛恶化 药物弥补的头痛（MOH）。因此，迫切需要新的非阿片类抗迁移代理商 具有新颖的作用机理。为此，我们旨在开发双重抑制剂，单个小分子 同时抑制两种与疼痛相关的酶：可溶性环氧化物水解酶（SEH）和脂肪酸酰胺水解酶 （faah​​）。这些化合物的最原始和机械上不同的方面是它们抑制两个化合物的能力 不同的酶在三角血管系统内在疼痛和炎症中起重要作用 同时地。此处描述的双重SEH/FAAH抑制剂有可能用作有前途的小说 非阿片类抗偏ra策策略。我们的本科生已经确定了几种非常有效的双重抑制剂 并在体内测试了我们的铅抑制剂，以证明急性炎性疼痛大鼠模型中的抗伤害感受。 我们还观察到，这种双重抑制剂比传统的NSAID产生抗伤害感受 酮洛芬，不会产生行为破坏性的副作用。在拟议的研究中，我们将严格 在偏头痛疼痛的大鼠模型中评估我们的两个铅双重抑制剂，合成和评估新的文库 旨在与两种靶酶同时相互作用的配体，评估抗偏流效应 在这些新配体中，并评估我们的双重抑制剂的给药是否产生类似阿片类药物的奖励 效果或药物过度使用头痛。我们建议研究的化合物代表了一种完全新颖的 非阿片类药物在抗偏ra剂治疗中的开创性努力。因为这个班级有不同的生物学靶标 从现有治疗中，它代表了解决与之相关的长期存在问题的机会 现有的抗毛因疗法（例如阿片类药物，曲普特人）。据我们所知，该提议是第一次尝试 使用双重SEH/FAAH抑制剂的策略作为一种合理的抗偏ra剂治疗策略。另外， 这些双重抑制剂背后的设计原理，合成和体内策略是真正的多学科， 严格，全面和创新。我们的研究将为未来的调查提供坚定的基础 使用这种双重配体策略作为偏头痛疼痛的治疗方法。该建议代表协作工作 在两个西班牙裔服务机构分别是加州州东湾和加州州富勒顿州的富勒顿，并在 圣路易斯华盛顿大学医学院临床药理学中心。我们的多学科 团队拥有专业知识和资源来解决该项目，以确保持续的成功。