Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and <i>N</i>-Acylethanolamine Acid Amidase Inhibitors

Tuo, Wei; Leleu-Chavain, Natascha; Spencer, John; Sansook, Supojjanee; Millet, Régis; Chavatte, Philippe

doi:10.1021/acs.jmedchem.6b00538

Cited by 95 publications

(95 citation statements)

References 182 publications

(795 reference statements)

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“…The non‐genomic effects of PEA may also involve the indirect activation of other receptors, such as cannabinoid receptors, mediated by anandamide (AEA) through the so‐called ‘entourage hypothesis’ (LoVerme et al ., ). In this context, competition by PEA for fatty acid amide hydrolase (FAAH)‐mediated hydrolysis, is thought to provide a ‘sparing effect’ on AEA hydrolysis by FAAH, resulting in enhanced signalling at endocannabinoid targets, in particular CB 1 or CB 2 receptors, to produce analgesia (Tuo et al ., ). In keeping with this, we have recently demonstrated a role for CB 1 receptors in the antinociceptive effects of PEA injected directly into the anterior cingulate cortex (ACC) in the rat formalin test (Okine et al ., ).…”

Section: Evidence From Pharmacological or Genetic Manipulation Studiementioning

confidence: 97%

PPARs and pain

Okine

Gaspar

Finn

2018

British J Pharmacology

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Chronic pain is a common cause of disability worldwide and remains a global health and socio-economic challenge. Current analgesics are either ineffective in a significant proportion of patients with chronic pain or associated with significant adverse side effects. The PPARs, a family of nuclear hormone transcription factors, have emerged as important modulators of pain in preclinical studies and therefore a potential therapeutic target for the treatment of pain. Modulation of nociceptive processing by PPARs is likely to involve both transcription-dependent and transcription-independent mechanisms. This review presents a comprehensive overview of preclinical studies investigating the contribution of PPAR signalling to nociceptive processing in animal models of inflammatory and neuropathic pain. We examine current evidence from anatomical, molecular and pharmacological studies demonstrating a role for PPARs in pain control. We also discuss the limited evidence available from relevant clinical studies and identify areas that warrant further research.

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Section: Evidence From Pharmacological or Genetic Manipulation Studiementioning

confidence: 97%

PPARs and pain

Okine

Gaspar

Finn

2018

British J Pharmacology

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“…Over the past decades, the inhibition of these enzymes emerged as therapeutic option for treating neuropsychiatric disorders, including major depression and anxiety (Batista et al, 2014; Ogawa and Kunugi, 2015). In fact, inhibiting MAGL or FAAH can prolong the homeostatic actions of released eCBs, thereby minimizing side effects from exogenous activation of CB 1 /CB 2 receptors (Petrosino and Di Marzo, 2010; Tuo et al, 2017). …”

Section: Endocannabinoid and Endovanilloid Systemsmentioning

confidence: 99%

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

et al. 2017

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Much of our knowledge of the endocannabinoid system in schizophrenia comes from behavioral measures in rodents, like prepulse inhibition of the acoustic startle and open-field locomotion, which are commonly used along with neurochemical approaches or drug challenge designs. Such methods continue to map fundamental mechanisms of sensorimotor gating, hyperlocomotion, social interaction, and underlying monoaminergic, glutamatergic, and GABAergic disturbances. These strategies will require, however, a greater use of neurophysiological tools to better inform clinical research. In this sense, electrophysiology and viral vector-based circuit dissection, like optogenetics, can further elucidate how exogenous cannabinoids worsen (e.g., tetrahydrocannabinol, THC) or ameliorate (e.g., cannabidiol, CBD) schizophrenia symptoms, like hallucinations, delusions, and cognitive deficits. Also, recent studies point to a complex endocannabinoid-endovanilloid interplay, including the influence of anandamide (endogenous CB1 and TRPV1 agonist) on cognitive variables, such as aversive memory extinction. In fact, growing interest has been devoted to TRPV1 receptors as promising therapeutic targets. Here, these issues are reviewed with an emphasis on the neurophysiological evidence. First, we contextualize imaging and electrographic findings in humans. Then, we present a comprehensive review on rodent electrophysiology. Finally, we discuss how basic research will benefit from further combining psychopharmacological and neurophysiological tools.

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“…24 MAGL inhibition also reduces levels of arachidonic acid (AA), a pain and inflammation-inducing prostaglandin precursor, and provides protection against neuroinflammation and neurodegenerative diseases. 25–29 Therefore, MAGL-based pharmacotherapy may provide an alternative and effective approach 30 to stimulate eCB and beneficial treatment in pain, anxiety, inflammation, neurodegeneration and cancer, 29, 31–34 without significant adverse effects, for example, mobility and cognition associated with direct CB 1 modulations. 4, 25, 35 …”

Section: Introductionmentioning

confidence: 99%

In Vitro and in Vivo Evaluation of ¹¹C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies

Cheng

Mori

et al. 2018

J. Med. Chem.

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Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand, 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including 11C-carbonylation and spirocyclic iodonium ylide (SCIDY) radiofluorination. The lead compound [11C]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.

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Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

Cited by 95 publications

References 182 publications

PPARs and pain

PPARs and pain

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

In Vitro and in Vivo Evaluation of ¹¹C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies

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Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

Cited by 95 publications

References 182 publications

PPARs and pain

PPARs and pain

Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research

In Vitro and in Vivo Evaluation of 11C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies

Contact Info

Product

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In Vitro and in Vivo Evaluation of ¹¹C-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies