Peripheral FAAH as a target for novel analgesics

外周 FAAH 作为新型镇痛药的靶点

• 批准号: 8455641
• 负责人: Miguel Garcia-Guzman
• 金额: $ 13.27万
• 依托单位: ANTEANA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8455641
• 关键词: Absence of pain sensation; Acute; Adverse effects; Adverse event; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Anticonvulsants; Arachidonic Acids; Attenuated; Behavior; Biological; Biology; Brain; CNR1 gene; California; Chemical Stimulation; Clinical; Colon; Complex Regional Pain Syndromes; Constipation; Data; Development; Dose; Endocannabinoids; Enzymes; Ethanolamines; Fiber; Funding; Genetic; Goals; Grant; Human; Hydrolysis; Hyperalgesia; Indomethacin; Industry; Knowledge; Marijuana; Mediating; Medical; Medicine; Modeling; Morphine; Mus; Nerve Fibers; Neuraxis; Neurons; Neurotransmitters; Nociception; Operative Surgical Procedures; Opiates; Oral; Pain; Pain management; Patients; Peripheral; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Postoperative Pain; Pre-Clinical Model; Preclinical Drug Development; Process; Property; Regulation; Research; Role; Safety; Sedation procedure; Series; Signal Transduction; Small Business Technology Transfer Research; Spinal Cord; Spinal cord posterior horn; Stomach; Testing; Tissues; Translating; Universities; Visceral pain; Work; afferent nerve; anandamide; brain cell; chronic pain; comparative efficacy; effective therapy; experience; fatty acid amide hydrolase; gabapentin; inhibitor/antagonist; innovation; irritation; member; mouse model; novel; novel therapeutics; pain inhibition; pre-clinical; prototype; public health relevance; receptor; receptor expression; transmission process

DESCRIPTION (provided by applicant): Pain management remains a significant unmet medical need. Anandamide is an endogenous marijuana-like ('endocannabinoid') molecule that plays important roles in the regulation of pain. Previous work has shown that endocannabinoid receptors located outside the central nervous system (CNS) exert a powerful regulatory control over pain initiation. Moreover, there is evidence that clinical conditions associated with chronic pain are accompanied by abnormal elevations in the peripheral levels of anandamide. The biological actions of anandamide are stopped by the intracellular enzyme, fatty acid amide hydrolase (FAAH), which catalyzes the deactivating hydrolysis of anandamide. To explore the role of peripheral anandamide in pain regulation, the lab of Daniele Piomelli at the University of California, Irvine, has developed a novel class of FAAH inhibitors that do not enter the CNS and therefore suppress anandamide deactivation only in the periphery of the body. The prototype member of this class is called URB937. URB937 is potent at attenuating pain-related behaviors in animal models, suggesting that it might offer a radically innovative approach to pain therapy. Our proposal has three primary goals aimed at testing this hypothesis: (1) Further characterize the analgesic properties of URB937. We will profile the effects of oral URB937 in industry-appropriate preclinical models of post-operative pain and visceral pain/referred hyperalgesia. (2) Compare the analgesic efficacy of URB937 with that of other analgesics. We will compare the efficacy of URB937 with that of clinically used analgesics, including opiates (morphine), non- steroidal anti-inflammatory drugs (indomethacin) and gabapentin. (3) Determine whether URB937 produces side effects similar to those caused by other analgesics. Clinically used analgesics cause a series of common side effects that include gastric irritation, constipation and sedation. Previous work in our lab has shown that URB937 produces no gastric irritation after oral dosing. We will test now whether URB937 causes constipation or sedation, using morphine and gabapentin as comparators. If the results of these studies show that URB937 is equal or superior to its comparators, we will apply for STTR Phase 2 funding to move forward the preclinical development of URB937.

描述（由申请人提供）：疼痛管理仍然是一个重要的未满足的医疗需求。Anandamide是一种内源性大麻样（内源性大麻素）分子，在疼痛调节中起重要作用。先前的研究表明，位于中枢神经系统（CNS）外的内源性大麻素受体对疼痛的引发具有强大的调节控制作用。此外，有证据表明，与慢性疼痛相关的临床状况伴随着外周anandamide水平的异常升高。anandamide的生物活性被胞内酶脂肪酸酰胺水解酶（FAAH）阻止，FAAH催化anandamide的失活水解。为了探索外周anandamide在疼痛调节中的作用，加州大学欧文分校的Daniele Piomelli实验室开发了一类新的FAAH抑制剂，它们不进入中枢神经系统，因此仅在身体外周抑制anandamide失活。这个类的原型成员叫做URB937。在动物模型中，URB937在减轻疼痛相关行为方面是有效的，这表明它可能为疼痛治疗提供一种根本性的创新方法。我们的建议有三个主要目标旨在验证这一假设：(1)进一步表征URB937的镇痛特性。我们将在符合行业标准的术后疼痛和内脏疼痛/牵涉性痛觉过敏临床前模型中研究口服URB937的效果。(2)比较URB937与其他镇痛药的镇痛效果。我们将比较URB937与临床常用镇痛药的疗效，包括阿片类药物（吗啡）、非甾体类抗炎药（吲哚美辛）和加巴喷丁。(3)判断URB937是否产生与其他镇痛药相似的副作用。临床使用的镇痛药会引起一系列常见的副作用，包括刺激胃、便秘和镇静。我们实验室以前的工作表明，口服URB937后不会产生胃刺激。我们现在将测试URB937是否引起便秘或镇静，使用吗啡和加巴喷丁作为对照。如果这些研究结果表明URB937与同类药物相同或优于同类药物，我们将申请STTR二期资助，推进URB937的临床前开发。