Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets

Zhang, Di; Saraf, Anita; Kolasa, Teodozyj; Bhatia, Pramila; Zheng, Guo Zhu; Patel, Meena; Lannoye, G.; Richardson, Paul L.; Stewart, Andrew O.; Rogers, John C.; Brioni, Jorge D.; Surowy, Carol S.

doi:10.1016/j.neuropharm.2006.11.009

Cited by 94 publications

(116 citation statements)

References 41 publications

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“…4c). URB597, the rather selective FAAH inhibitor Zhang et al 2007) These results show that PEA hydrolysis in BV-2 cell homogenates is mediated by a serine hydrolase activity that is sensitive to both URB597 and URB602.…”

Section: Resultsmentioning

confidence: 63%

Microglia produce and hydrolyze palmitoylethanolamide

Muccioli

Stella

2008

Neuropharmacology

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Microglial cell activation and migration play an important role in neuroinflammation propagation. While it is known that the lipid transmitter palmitoylethanolamide (PEA) regulates microglial migration by interacting with a cannabinoid-like receptor, the production and inactivation of this lipid by microglia has never been addressed directly. Here we show that the mouse microglial cell line BV-2 produces and hydrolyzes PEA. The carbamate compound URB602 inhibits PEA hydrolysis in BV-2 cell homogenates and increases PEA levels in intact cells, whereas the FAAH inhibitor URB597 and serine-hydrolase inhibitor MAFP do not affect PEA levels in intact cells. This unique pharmacological profile of inhibitors on PEA hydrolysis suggests the involvement of a previously undescribed enzyme that degrades PEA. This enzyme expressed by microglia constitutes a promising target for controlling the propagation of neuroinflammation.

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Section: Resultsmentioning

confidence: 63%

Microglia produce and hydrolyze palmitoylethanolamide

Muccioli

Stella

2008

Neuropharmacology

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“…None of the compounds presented significantly inhibited MGL activity. Since the carbamate based FAAH inhibitors have been reported to have several off-targets [19,25,51] the selectivity of chiral 3-oxazolinylphenyl N-alkylcarbamates would be important issue to study in more detail in the future. In molecular modelling studies, the combined docking and molecular interaction field analysis emphasized the importance of heterocycle interaction with Cys269 and Val270 of FAAH, and also highlighted the steric features of the FAAH active site.…”

Section: Resultsmentioning

confidence: 99%

Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Myllymäki¹,

Käsnänen

Kataja³

et al. 2009

European Journal of Medicinal Chemistry

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Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein-ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)-and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.

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“…71 Nevertheless, compound 30 was shown to inactivate carboxylesterases and block the expression of tyrosine hydroxylase as off-target effects. 72,73 It manifested potent anxiolytic properties without affecting appetite or body temperature in models of elevated zero-maze and the isolation-induced ultrasonic emission in rats (0.1-0.3 mg/kg intraperitoneal injection) and produced pain relief in the complete…”

Section: Carbamatesmentioning

confidence: 99%