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- Deplano, Alessandro, et al.
(författare)
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Novel propanamides as fatty acid amide hydrolase inhibitors
- 2017
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 136, s. 523-542
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Tidskriftsartikel (refereegranskat)abstract
- Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroary1)-2-(4(2-(trifluoromethyl)pyridin-4-y0amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or noncompetitive (TPA14) inhibition modes.
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- Karlsson, Jessica, et al.
(författare)
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Interaction of the N-(3-Methylpyridin-2-yl) amide Derivatives of Flurbiprofen and Ibuprofen with FAAH : Enantiomeric Selectivity and Binding Mode
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Background Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here. Methodology/Principal Findings FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAH(T488A)-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)-and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 mu M, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 mu M) was more potent than the (R)-enantiomer (IC50 5.7 mu M). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH. Conclusions/Significance The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors.
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- Matus, M., et al.
(författare)
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Key Comparison EURAMET.L-K1.2011 Measurement of gauge blocks by interferometry
- 2016
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Ingår i: Metrologia. - 0026-1394 .- 1681-7575. ; 53:1A
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Tidskriftsartikel (refereegranskat)abstract
- The key comparison EURAMET.L-K1.2011 on gauge blocks was carried out in the framework of a EURAMET project starting in 2012 and ending in 2015. It involved the participation of 24 National Metrology Institutes from Europe and Egypt, respectively. 38 gauge blocks of steel and ceramic with nominal central lengths between 0.5 mm and 500 mm were circulated. The comparison was conducted in two loops with two sets of artifacts. A statistical technique for linking the reference values was applied. As a consequence the reference value of one loop is influenced by the measurements of the other loop although they did not even see the artifacts of the others. This influence comes solely from three "linking laboratories" which measure both sets of artifacts. In total there were 44 results were not fully consistent with the reference values. This represents 10% of the full set of 420 results which is a considerable high number. At least 12 of them are clearly outliers where the participants have been informed by the pilot as soon as possible. The comparison results help to support the calibration and measurement capabilities (CMCs) of the laboratories involved in the CIPM MRA.
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