Abstract
Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)-2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.
Keywords:
FAAH inhibition; Ibuprofen amides; cyclooxygenase; endocannabinoid; fatty acid amide hydrolase.
MeSH terms
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Amides / chemical synthesis
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Amides / chemistry
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Amides / pharmacology*
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / metabolism
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Animals
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Cyclooxygenase 1 / metabolism*
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Cyclooxygenase 2 / metabolism*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Ibuprofen / chemical synthesis
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Ibuprofen / chemistry
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Ibuprofen / pharmacology*
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Molecular Docking Simulation
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Molecular Structure
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Structure-Activity Relationship
Substances
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Amides
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Enzyme Inhibitors
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Cyclooxygenase 1
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Cyclooxygenase 2
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Amidohydrolases
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fatty-acid amide hydrolase
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Ibuprofen
Grants and funding
C.F. would like to thank the Research Funds of the Medical Faculty, Umeå University, for financial support. V.O would like to thank the Regione Autonoma della Sardegna Project L.R. 7/2007 under grant no. 2012_CRP-59473 and the University of Cagliari (grant FIR 2018–19). B.C. would like to thank Regione Campania under grant B61C17000070007- SATIN (POR Campania FESR 2014/2020). This work was supported by the Open Access Publishing Fund of the University of Cagliari, with the funding of the Regione Autonoma della Sardegna – L.R. n. 7/2007.