Peripheral FAAH as a target for novel analgesics

描述(由申请人提供)：疼痛管理仍然是一个重要的未得到满足的医疗需求。阿南达胺是一种内源性的大麻样分子，在疼痛的调节中发挥重要作用。以往的工作表明，位于中枢神经系统(CNS)外的内源性大麻素受体对疼痛的启动具有强大的调控作用。此外，有证据表明，与慢性疼痛相关的临床状况伴随着外周血中ANANDAME水平的异常升高。脂肪酸酰胺水解酶(FAAH)是一种胞内酶，它催化苯二胺的失活水解酶，从而停止了它的生物学作用。加州大学欧文分校Daniele Piomelli的实验室为了探索外周ANANDAME在疼痛调节中的作用，开发了一类新型的FAAH抑制剂，这种抑制剂不进入中枢神经系统，因此只在身体外周抑制ANANDAME失活。这个类的原型成员称为URB937。URB937在减轻动物模型中的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，旨在检验这一假说：(1)进一步表征URB937的止痛特性。我们将介绍口服URB937在适合行业的术后疼痛和内脏疼痛/牵涉痛觉过敏的临床前模型中的效果。(2)比较URB937与其他镇痛剂的镇痛效果。我们将比较URB937与临床使用的止痛药的疗效，包括阿片类药物(吗啡)、非类固醇抗炎药(吲哚美辛)和加巴喷丁。(3)确定URB937是否产生与其他镇痛剂类似的副作用。临床使用的止痛药会引起一系列常见的副作用，包括胃刺激、便秘和镇静。我们实验室以前的工作表明，URB937口服后不会对胃产生刺激。我们现在将以吗啡和加巴喷丁为对照，测试URB937是否会导致便秘或镇静。如果这些研究的结果显示，市建局937与其比较指标相若或更优，我们会申请沙田医院第二期拨款，以推动市建局937的临床前发展。

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.