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

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Abstract 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. We analysed the affinity of ODA, ArDA and SyDA at the FAAH-1 in vitro and investigated the potency of selected NSAIDs on the hydrolysis of endocannabinoid-like molecules (ODA, ArDA and SyDA) 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. The substrate affinity of FAAH-1 obtained, increased in a rank order of ODA < ArDA < SyDA with resultant Vmax values in a rank order of ArDA > ODA > SyDA. 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 ODA and ArDA by meclofenamate and indomethacin to be non-competitive in nature. Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.

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