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

项目总结/摘要 偏头痛是世界上最常见的神经系统疾病，其特征是严重头痛发作 并伴有恶心、呕吐和活动抑制等多种症状。尽管 偏头痛的发病率，治疗偏头痛是穷人。非特异性镇痛药，如阿片类药物和非甾体类抗- 消炎药（NSAIDs）产生止痛作用，但反复使用可能产生成瘾和胃溃疡， 分别偏头痛的传统治疗方法，如曲坦类（5-羟色胺受体激动剂）， 副作用，而反复使用某些抗偏头痛治疗恶化头痛的条件下， 药物过度使用性头痛（MOH）因此，迫切需要新的非阿片类抗偏头痛剂 with novel新mechanisms机制of action行动.为此，我们的目标是开发双重抑制剂，单一的小分子， 同时抑制两种疼痛相关酶：可溶性环氧化物水解酶（sEH）和脂肪酸酰胺水解酶 （FAAH）。这些化合物最原始和机制上不同的方面是它们抑制两种 在三叉神经血管系统内的疼痛和炎症中发挥重要作用的不同酶 同步这里描述的双重sEH/FAAH抑制剂有可能被用作一种有前途的新药物。 非阿片类抗偏头痛策略。我们的本科生已经发现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，以证明在急性炎性疼痛的大鼠模型中的抗伤害感受。 我们还观察到这种双重抑制剂在比传统NSAID更低的剂量下产生抗伤害感受作用 酮洛芬并且不产生行为破坏性副作用。在这些研究中，我们将严格 在偏头痛大鼠模型中评估我们的两种先导双重抑制剂，合成和评估新的 设计与两种靶酶同时相互作用的配体，评估抗偏头痛作用 这些新的配体，并评估是否管理我们的双重抑制剂产生阿片样奖励 影响或药物过度使用头痛。我们建议研究的化合物代表了一种全新的 非阿片类药物，在抗偏头痛治疗方面的开创性努力。因为这门课有不同的生物学目标 从现有的治疗方法，它代表了一个机会，以解决长期存在的问题，已被链接到 现有的抗偏头痛疗法（例如，阿片类药物、曲坦类药物）。据我们所知，这一建议是第一次尝试 使用sEH/FAAH双重抑制剂作为合理的抗偏头痛治疗策略。此外该 这些双重抑制剂背后的设计原理、合成和体内策略是真正多学科的， 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治疗偏头痛。这项提案代表了合作工作 两个西班牙裔服务机构，加州州立大学东湾和加州州立大学富勒顿之间，从指导 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这个即将到来的项目，以确保持续的成功。

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.