Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin.

@article{Holt2007InhibitionOF,
  title={Inhibition of fatty acid amide hydrolase, a key endocannabinoid metabolizing enzyme, by analogues of ibuprofen and indomethacin.},
  author={Sandra Holt and Ben Paylor and Linda Boldrup and Kirsi Alajakku and S{\'e}verine Vandevoorde and A K Sundstr{\"o}m and Maria Teresa Cocco and Valentina Onnis and Christopher John Fowler},
  journal={European journal of pharmacology},
  year={2007},
  volume={565 1-3},
  pages={
          26-36
        }
}
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65 Citations
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65 Citations

Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor that reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals.

Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide

Eight ibuprofen analogues were investigated and compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists.

Inhibition of Endocannabinoid Metabolism by the Metabolites of Ibuprofen and Flurbiprofen

It is concluded that the primary metabolites of ibuprofen and flurbiprofen retain some of the properties of the parent compound with respect to inhibition of endocannabinoid metabolism, however, these effects are unlikely to contribute to the actions of theparent compounds in vivo.

The fatty acid amide hydrolase and cyclooxygenase-inhibitory properties of novel amide derivatives of carprofen.

Synthesis and evaluation of paracetamol esters as novel fatty acid amide hydrolase inhibitors.

The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described, and it is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.

Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen.

Novel propanamides as fatty acid amide hydrolase inhibitors.

Discovery and development of endocannabinoid-hydrolyzing enzyme inhibitors.

The inactivation of FAAH and MGL by specific enzyme inhibitors increases the levels of AEA and 2-AG, respectively, producing therapeutic effects such as pain relief and depression of anxiety.

Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.

  • S. Vandevoorde
  • Biology, Chemistry
    Current topics in medicinal chemistry
  • 2008
The purpose of this review is to give an overview of the families of synthetic inhibitors of FAAH and MAGL, which contain few members and most of them exhibit a lack of selectivity.

Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents

Flu-AM4 is identified as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models, underscore the potential usefulness of such dual- action compounds.
...

References

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Acidic Nonsteroidal Anti-inflammatory Drugs Inhibit Rat Brain Fatty Acid Amide Hydrolase in a pH-dependent Manner

The data are consistent with the conclusion that the non-ionised forms of the acidic NSAIDs are responsible for the inhibition of fatty acid amide hydrolase.

Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors.

Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors and eliminating the gastrointestinal side effects of the parent compound.

The potency of the fatty acid amide hydrolase inhibitor URB597 is dependent upon the assay pH.

Synergistic antinociceptive effects of anandamide, an endocannabinoid, and nonsteroidal anti-inflammatory drugs in peripheral tissue: a role for endogenous fatty-acid ethanolamides?

Modifications of the ethanolamine head in N-palmitoylethanolamine: synthesis and evaluation of new agents interfering with the metabolism of anandamide.

It is concluded that although none of the PEA derivatives were dramatically more potent than PEA itself at reducing the metabolism of AEA, the lack of effect of the compounds at CB(1) and CB(2) receptors makes them useful templates for development of possible therapeutic FAAH inhibitors.

Inhibition of anandamide hydrolysis by the enantiomers of ibuprofen, ketorolac, and flurbiprofen.

There is no dramatic enantiomeric selectivity of NSAID compounds as inhibitors of fatty acid amide hydrolase enzyme(s) responsible for the hydrolysis of anandamide, and the enantiomers of flurbiprofen and R-ketorolac are the most potent NSAID inhibitors of omega-3 acid Hydrolase yet reported.

Anandamide metabolism by fatty acid amide hydrolase in intact C6 glioma cells. Increased sensitivity to inhibition by ibuprofen and flurbiprofen upon reduction of extra- but not intracellular pH

It is concluded that a reduction of extracellular pH produces an enhanced accumulation of the acidic NSAIDs ibuprofen and flurbiprofen into C6 glioma cells and thereby an inhibition of anandamide metabolism.

Local interactions between anandamide, an endocannabinoid, and ibuprofen, a nonsteroidal anti-inflammatory drug, in acute and inflammatory pain

Effects of pH on the inhibition of fatty acid amidohydrolase by ibuprofen

The higher potency of ibuprofen at lower pH values raises the possibility that in certain types of inflamed tissue, the concentration of this compound following oral administration may be sufficient to inhibit FAAH.

Purification and Characterization of an Acid Amidase Selective for N-Palmitoylethanolamine, a Putative Endogenous Anti-inflammatory Substance*

The new enzyme referred to as N-palmitoylethanolamine hydrolase was clearly distinguishable from anandamide amidohydrolase and was the most active at pH 5 and was activated 7-fold by Triton X-100.