Abstract

BackgroundPain 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.MethodsWe 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.ResultsThe 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-competitive in nature.ConclusionOur data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.

Highlights

  • IntroductionFatty acid amide hydrolase I (FAAH-1) has been proposed as a promising target for the discovery of drugs to treat pain, inflammation and other pathologies [3, 4]

  • Several therapeutic agents have been designed to address different forms of pain, yet pain relief remains an area of significant unmet patient need [1, 2]

  • FAAH-1 is the primary enzyme that is responsible for the degradation of N –Arachidonoyl ethanolamide (Anandamide, AEA) and related fatty acid amides which constitute a group of biologically active endogenous amides [5, 6]

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Summary

Introduction

Fatty acid amide hydrolase I (FAAH-1) has been proposed as a promising target for the discovery of drugs to treat pain, inflammation and other pathologies [3, 4]. FAAH-1 is the primary enzyme that is responsible for the degradation of N –Arachidonoyl ethanolamide (Anandamide, AEA) and related fatty acid amides which constitute a group of biologically active endogenous amides [5, 6]. 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. The metabolism of endocannabinoids by COX-2 was suggested to be differentially regulated by NSAIDs

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