The endocannabinoid system plays a critical role in modulating both peripheral and central nervous system function. Despite being present throughout the animal kingdom, there has been relatively little investigation of the endocannabinoid system beyond traditional animal models. In this study, we report on the identification and characterization of a putative fatty acid amide hydrolase (FAAH) in the medicinal leech, Hirudo verbana. FAAH is the primary enzyme responsible for metabolizing the endocannabinoid signaling molecule arachidonoyl ethanolamide (anandamide or AEA) and therefore plays a critical role in regulating AEA levels in the nervous system. mRNA encoding Hirudo FAAH (HirFAAH) is expressed in the leech central nervous system (CNS) and sequence analysis suggests that this is an orthologue of FAAH-2 observed in vertebrates. Functionally, HirFAAH has serine hydrolase activity based on activity-based protein profiling (ABPP) studies using the fluorophosphonate probe TAMRA-FP. HirFAAH also hydrolyzes arachidonyl 7-amino, 4-methyl coumarin amide (AAMCA), a substrate specific to FAAH. Hydrolase activity during both the ABPP and AAMCA assays was eliminated by a mutation at a conserved catalytic serine. Activity was also blocked by the known FAAH inhibitor, URB597. Treatment of Hirudo ganglia with URB597 potentiated synapses made by the pressure-sensitive mechanosensory neuron (P cell), mimicking the effects of exogenously applied AEA. The Hirudo CNS has been a useful system in which to study properties of endocannabinoid modulation of nociception relevant to vertebrates. Therefore, this characterization of HirFAAH is an important contribution to comparative studies of the endocannabinoid system.

2024-06-28·ACS Sensors

Monofluorophore-based Two-Photon Ratiometric Fluorescent Probe for the Quantitative Imaging of Fatty Acid Amide Hydrolase in Live Neurons and Mouse Brain Tissues

Article

作者: Cai, Wenyan ; Gu, Xin ; Han, Yujie ; Zhang, Qi-Wei ; Wang, Xuewei

Fatty acid amide hydrolase (FAAH) plays a crucial role in the metabolism of the endocannabinoid system by hydrolyzing a series of bioactive amides, whose abnormal levels are associated with neuronal disorders including Alzheimer's disease (AD). However, due to the lack of suitable quantitative sensing tools, real-time and accurate monitoring of the activity of FAAH in living systems remains unresolved. Herein, a novel enzyme-activated near-infrared two-photon ratiometric fluorescent probe (CANP) based on a naphthylvinylpyridine monofluorophore is successfully developed, in which the electron-withdrawing amide moiety is prone to be hydrolyzed to an electron-donating amine group under the catalysis of FAAH, leading to the activation of the intramolecular charge transfer process and the emergence of a new 80 nm red-shifted emission, thereby achieving a ratiometric luminescence response. Benefiting from the high selectivity, high sensitivity, and ratiometric response to FAAH, the probe CANP is successfully used to quantitatively monitor and image the FAAH levels in living neurons, by which an amyloid β (Aβ)-induced upregulation of endogenous FAAH activity is observed. Similar increases in FAAH activity are found in various brain regions of AD model mice, indicating a potential fatty acid amide metabolite-involved pathway for the pathological deterioration of AD. Moreover, our quantitative FAAH inhibition experiments further demonstrate the great value of CANP as an efficient visual probe for in situ and precise assessment of FAAH inhibitors in complex living systems, assisting the discovery of FAAH-related therapeutic agents.

2024-04-01·Progress in neuro-psychopharmacology & biological psychiatry

Social stress-induced depressive-like symptoms and changes in gut microbial and lipidomic profiles are prevented by pharmacological inhibition of FAAH activity in male rats

Article

作者: Turroni, Francesca ; Ferlenghi, Francesca ; Mor, Marco ; Carnevali, Luca ; Viglioli, Martina ; Ventura, Marco ; Mancabelli, Leonardo ; Vacondio, Federica ; Barbetti, Margherita ; Rivara, Silvia ; Longhi, Giulia ; Sgoifo, Andrea

Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity has antidepressant-like effects in preclinical models of stress. In this study, we investigated whether the antidepressant-like effects of FAAH inhibition are associated with corresponding changes in gut microbial and lipidomic profiles, which are emerging as critical components in the pathophysiology of depression. Adult male Wistar rats experienced five weeks of repeated social defeat or control procedure and were treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle starting from the third week. Repeated social defeat induced the emergence of depressive-like behavioral (sucrose preference reduction and passive coping behaviors in the forced swim test) and neuroendocrine (increased corticosterone levels) changes, which were prevented by URB694 treatment. Repeated social defeat also provoked a significant variation in gut microbiota (changes in the relative abundance of 14 bacterial taxa) and lipidic (e.g., glycerophospholipids) composition. These stress-induced changes were prevented by URB694 treatment. These findings indicate that inhibition of FAAH activity with URB694 blocks the co-occurrence of depressive-like behavioral and neuroendocrine changes and alterations in gut microbial and lipid composition in rats exposed to repeated social defeat. In conclusion, these results suggest that the gut microbiota-lipid crosstalk may represent a novel biological target for FAAH inhibitors to enhance stress resilience.

项与 IPI-940 相关的新闻（医药）

2022-07-15

·医药观澜

治疗重度抑郁症！雅培深部脑刺激系统获FDA突破性医疗器械认定

▎药明康德内容团队报道7月13日，雅培（Abbott）宣布，美国FDA授予该公司的深部脑刺激（deep brain stimulation，DBS）系统突破性医疗器械认定，用于治疗难治性抑郁症（TRD）。公开资料显示，DBS疗法是过去二十年里临床神经科学最重要的进步之一。它是通过神经外科手术，在患者受疾病影响的脑区放置电极，提供一定的电刺激，帮助大脑控制运动。目前，DBS已经在临床中用于治疗帕金森病和特发性震颤等神经系统疾病的运动相关症状。研究表明，DBS也是治疗重度抑郁症等精神疾病的一种潜在方法。TRD是一种重度抑郁症。目前，治疗重度抑郁症的主要方法是使用抗抑郁药物，这通常需要服药十至十二周才能实现实质性症状缓解。而且通常，患者需要持续服用抗抑郁药物至少一年。尽管临床上已经有了诸多抗抑郁药物和医疗设备，然而仍有高达1/3的重度抑郁症患者在尝试了四种以上不同的抗抑郁疗法之后仍然无法得到缓解，导致发展为TRD，这些患者通常面临极高的疾病复发率。雅培的DBS系统是一种可由患者调节的个性化治疗方法，它将细导线植入大脑的目标区域，同时，植入胸部皮肤下的脉冲发生器与电极导线连接，产生电脉冲，从而调节异常的大脑活动。根据雅培公开资料，早先这款DBS系统已经获批用于治疗帕金森病、成人特发性震颤、难治性肌张力障碍等（商品名为Infinity），帮助控制运动障碍患者的症状。但有证据表明，在大脑中调节情绪的部分植入电极也有助于减轻TRD的症状。雅培正在制定研究计划，评估该系统针对TRD患者的疗效和安全性。此外，这款DBS系统可以与名为NeuroSphere的虚拟诊所配合使用，后者是一种连接式护理技术，可以允许患者与医生远程交流，从而使患者可以在自己家中接受治疗。雅培新闻稿表示，本次该DBS系统获得FDA授予突破性医疗器械认定，意味着FDA将加快对该设备的监管审查，使其能尽快造福难治性抑郁症患者。参考资料：[1]UABBOTT RECEIVES FDA'S BREAKTHROUGH DEVICE DESIGNATION TO EXPLORE USE OF DEEP BRAIN STIMULATION TO MANAGE SEVERE DEPRESSION. Retrieved July 13 , 2022. From https://abbott.mediaroom.com/2022-07-12-Abbott-Receives-FDAs-Breakthrough-Device-Designation-to-Explore-Use-of-Deep-Brain-Stimulation-to-Manage-Severe-Depression[2]ST. JUDE MEDICAL INFINITY™ DBS SYSTEM. From https://www.neuromodulation.abbott/us/en/hcp/products/dbs-movement-disorders/st-jude-medical-infinity-dbs-system.html?clset=af584191-45c9-4201-8740-5409f4cf8bdd%3ab20716c1-c2a6-4e4c-844b-d0dd6899eb3a本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

突破性疗法

2021-05-11

·BioSpace

Autobahn Therapeutics Acquires Clinical-Stage FAAH Inhibitor from Astellas, Strengthening its Brain Targeting Chemistry Platform

May 11, 2021 12:30 UTC SAN DIEGO--(BUSINESS WIRE)--Autobahn Therapeutics, a biotechnology company focused on restoring hope for people affected by CNS disorders, today announced it has acquired global rights to ASP3652, a novel oral peripherally restricted fatty acid amide hydrolase (FAAH) inhibitor from Astellas Pharma Inc. ASP3652 complements Autobahn’s brain-targeting chemistry platform, which uses FAAH-mediated prodrug conversion to enable delivery of small molecules across the blood brain barrier. Peripheral blockade of FAAH activity further improves selective brain delivery of Autobahn’s compounds and enhances the ability to tailor a drug’s biodistribution to match the pathophysiology of various disorders. ASP3652 may be developed in combination with multiple pipeline programs, including with Autobahn’s proprietary selective thyroid hormone receptor beta (TRβ) agonists for the treatment of multiple sclerosis (MS). “We are excited by the addition of ASP3652 to our portfolio, which represents a very unique opportunity to enhance central delivery of our next-generation brain-targeting prodrugs for devastating CNS disorders, particularly MS,” said Kevin Finney, chief executive officer of Autobahn. “While there have been numerous advancements in the care of patients with MS, we believe there is a tremendous need for new therapeutic agents targeting remyelination. Based on the data demonstrated to date with ASP3652, we believe its combination with our novel TRβ prodrugs, represents a promising fit-for-purpose and a first-in-class therapeutic approach for MS and enables us to accelerate our development timeline. We are preparing for its continued evaluation as we work to bring novel treatments to patients in need.” ASP3652 has been previously evaluated in ten clinical studies dosing over 200 unique persons, demonstrating a favorable safety pro well as elevation of the endogenous substrate anandamide to 24 hours post-dose. This suggests that once-daily dosing of ASP3652 may be sufficient to limit peripheral hydrolysis of Autobahn prodrugs and enhance the therapeutic index of multiple programs. Autobahn has acquired global intellectual property, development and regulatory rights to ASP3652. About Autobahn Therapeutics Autobahn Therapeutics is focused on restoring hope for people affected by CNS disorders. Autobahn is leveraging its brain-targeting chemistry platform to unlock new therapeutic opportunities through precision tuning of the central exposure of its molecules. The company’s pipeline is led by ABX-002, a thyroid hormone receptor beta agonist for the treatment of adrenomyeloneuropathy (AMN), a rare genetic disorder. Autobahn Therapeutics is based in San Diego. For more information, visit .

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适应症	最高研发状态	国家/地区	公司	日期
炎症性疼痛	临床1期	美国	Infinity Pharmaceuticals, Inc.	-
神经痛	临床1期	美国	Infinity Pharmaceuticals, Inc.	-
神经痛	临床1期	-	Infinity AS	-