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|Title:||ASSESSMENT OF NSAIDS AS POTENTIAL INHIBITORS OF THE FATTY ACID AMIDE HYDROLASE I (FAAH-1) USING THREE DIFFERENT PRIMARY FATTY ACID AMIDE SUBSTRATES IN VITRO|
|Authors:||Dongdem, J. T.|
Helegbe, G. K.
Wezena, C. A.
|Publisher:||BioMed Central Ltd|
|Series/Report no.:||Vol. 23;Issue 1|
|Abstract:||Background: Pain relief remains a major subject of inadequately met need of patients. Therapeutic agents designed to treat pain and inflammation so far have low to moderate efficiencies with significant untoward side effects. FAAH-1 has been proposed as a promising target for the discovery of drugs to treat pain and inflammation without significant adverse effects. FAAH-1 is the primary enzyme accountable for the degradation of AEA and related fatty acid amides. Studies have revealed that the simultaneous inhibition of COX and FAAH-1 activities produce greater pharmacological efficiency with significantly lowered toxicity and ulcerogenic activity. Recently, the metabolism of endocannabinoids by COX-2 was suggested to be differentially regulated by NSAIDs. Methods: We analysed the affinity of oleamide, arachidonamide and stearoylamide at the FAAH-1 in vitro and investigated the potency of selected NSAIDs on the hydrolysis of endocannabinoid-like molecules (oleamide, arachidonamide and stearoylamide) by FAAH-1 from rat liver. NSAIDs were initially screened at 500 μM after which those that exhibited greater potency were further analysed over a range of inhibitor concentrations. Results: The substrate affinity of FAAH-1 obtained, increased in a rank order of oleamide < arachidonamide < stearoylamide with resultant Vmax values in a rank order of arachidonamide > oleamide > stearoylamide. The selected NSAIDs caused a concentration-dependent inhibition of FAAH-1 activity with sulindac, carprofen and meclofenamate exhibiting the greatest potency. Michaelis-Menten analysis suggested the mode of inhibition of FAAH-1 hydrolysis of both oleamide and arachidonamide by meclofenamate and indomethacin to be non ompetitive in nature. Conclusion: Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.|
|Appears in Collections:||School of Medicine and Health Sciences|
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