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，其特征是阵发性严重头痛。 伴有各种症状，如恶心、呕吐和活动抑制。尽管它的 虽然偏头痛的发病率很高，但治疗效果很差。非特异性止痛药，如阿片类药物和非类固醇抗痛药 炎症药物(非甾体类抗炎药)可以缓解疼痛，但反复服用可能会导致上瘾和胃溃疡， 分别进行了分析。传统的偏头痛治疗方法，如曲普坦(5-羟色胺受体激动剂)，受到 副作用，而重复使用某些抗偏头痛治疗会加剧头痛，这种情况被称为 用药过度头痛(MOH)。因此，迫切需要新的非阿片类抗偏头痛药物。 具有新的作用机制。为此，我们的目标是开发双重抑制剂，即单分子小分子 同时抑制两种与疼痛相关的酶：可溶性环氧化物水解酶(SEH)和脂肪酰胺水解酶 (FAAH)。这些化合物最原始和机械上最独特的方面是它们能够抑制两种 三叉神经血管系统中在疼痛和炎症中起重要作用的不同酶 同时。本文描述的双重sEH/FAAH抑制剂具有作为一种有前途的新型药物的潜力 非阿片类药物抗偏头痛策略。我们的本科生已经确定了几种非常有效的双重抑制物 并在体内测试了我们的铅抑制剂，以在急性炎症性疼痛的大鼠模型中展示抗伤害作用。 我们还观察到，这种双重抑制剂比传统的非甾体抗炎药在更低的剂量下产生抗伤害效应 酮洛芬，不会产生行为破坏性副作用。在拟议的研究中，我们将严格执行 在偏头痛大鼠模型中评价我们的两种先导双重抑制剂，合成和评价新的 被设计为同时与两种靶酶相互作用的配体，评估抗偏头痛的效果 这些新的配体，并评估我们的双重抑制剂的管理是否产生阿片样奖赏 效果或用药过度头痛。我们打算研究的化合物代表了一种全新的 非阿片类药物，在抗偏头痛治疗中的开创性努力。因为这个类有不同的生物目标 从现有的治疗方法来看，它代表着一个解决长期存在的问题的机会 现有的抗偏头痛疗法(如阿片类药物、曲普坦)。据我们所知，这项建议是第一次尝试 将sEH/FAAH双抑制剂作为一种合理的抗偏头痛治疗策略。此外， 这些双重抑制剂背后的设计原则、合成和体内策略确实是多学科的， 严谨、全面、创新。我们的研究将为今后的研究提供坚实的基础 使用这种双配体策略作为偏头痛的治疗方法。该提案代表了协作工作 在两个为拉美裔服务的机构之间，加州州立大学东湾分校和加州州立大学富勒顿分校，由 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即将到来的项目，以确保持续成功。