The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Fowler, Christopher J.

doi:10.1007/978-3-319-20825-1_4

Cited by 42 publications

(23 citation statements)

References 163 publications

(133 reference statements)

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“…It is apparent that FAAH-1 is a key controller of AEA tone in vivo , and therefore many inhibitors have been developed over the last decade to block its activity, thus enhancing content and biological activity of AEA. Despite the potential of these compounds as innovative therapeutics (reviewed by Bisogno and Maccarrone, 2013; Fowler, 2015), better drugs are still needed for effective cure or slowing down of human pathologies. In this context, it seems noteworthy that subtle differences exist between rodent and human FAAH-1 that impact on the efficacy of inhibitors, thus leading to rodent/human ratios of IC 50 values from ~0.3 to ~4.0 (Di Venere et al, 2012).…”

Section: Open Questions and Future Directionsmentioning

confidence: 99%

Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

Maccarrone

2017

Front. Mol. Neurosci.

145

151

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Cannabis extracts have been used for centuries, but its main active principle ∆9-tetrahydrocannabinol (THC) was identified about 50 years ago. Yet, it is only 25 years ago that the first endogenous ligand of the same receptors engaged by the cannabis agents was discovered. This “endocannabinoid (eCB)” was identified as N-arachidonoylethanolamine (or anandamide (AEA)), and was shown to have several receptors, metabolic enzymes and transporters that altogether drive its biological activity. Here I report on the latest advances about AEA metabolism, with the aim of focusing open questions still awaiting an answer for a deeper understanding of AEA activity, and for translating AEA-based drugs into novel therapeutics for human diseases.

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Section: Open Questions and Future Directionsmentioning

confidence: 99%

Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

Maccarrone

2017

Front. Mol. Neurosci.

145

151

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“…(7) for a review). Because of its critical role in adjusting AEA concentrations (8–11), FAAH has been the topic of a growing number of investigation and drug development (12–15) and is being actively investigated as a therapeutic target for CUD (16–18). …”

Section: Introductionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Boileau

Mansouri

Williams

et al. 2016

Biological Psychiatry

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Background One of the major mechanisms for terminating the actions of the endocannabinoid anandamide is hydrolysis by fatty acid amide hydrolase (FAAH) and inhibitors of the enzyme were suggested as potential treatment for human cannabis dependence. However, the status of brain FAAH in cannabis use disorder is unknown. Methods Brain FAAH binding was measured with positron emission tomography and [11C]CURB in 22 healthy control subjects and ten chronic, frequent cannabis users during early abstinence. The FAAH genetic polymorphism (rs324420) and blood, urine and hair levels of cannabinoids and metabolites were determined. Results In cannabis users FAAH binding was significantly lower by 14–20% across the brain regions examined as compared to matched control subjects (overall Cohen’s d=0.96). Lower binding was negatively correlated with cannabinoid concentrations in blood and urine and was associated with higher trait impulsiveness. Conclusions Lower FAAH binding levels in the brain may be a consequence of chronic and recent cannabis exposure and could contribute to cannabis withdrawal. This effect should be considered in the development of novel treatment strategies for cannabis use disorder that target FAAH and endocannabinoids. Further studies are needed to examine possible changes in FAAH binding during prolonged cannabis abstinence and whether lower FAAH binding predates drug use.

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“…To elucidate the neurobiological properties of other elements belonging to the endocannabinoid system, such as anandamide's major metabolic enzyme Fatty Acid Amide Hydrolase (FAAH), several studies have been aimed to describe the effects of FAAH in multiple experimental paradigms (Chauvet et al, 2015;Fowler, 2015;Panlilio et al, 2016), including experiments in sleep. For instance, FAAH-KO mice display no significant differences in sleep rebound after prolonged waking sessions (Huitro´n-Rese´ndiz et al, 2004) whereas studies outline that levels of expression of FAAH are lower in the brain after sleep deprivation in naı¨ve animals (Wang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

et al. 2016

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Abstract-The endocannabinoid system comprises receptors (CB 1 and CB 2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB 1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20 mg/kg; ip; separately each one) into rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD) while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB 1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking. Ó

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The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review

Cited by 42 publications

References 163 publications

Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

Fatty Acid Amide Hydrolase Binding in Brain of Cannabis Users: Imaging With the Novel Radiotracer [11C]CURB

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

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