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

• Published in: BMC pharmacology & toxicology Vol. 23; no. 1; pp. 1 - 11
• Main Authors: Dongdem, Julius T., Helegbe, Gideon K., Opare-Asamoah, Kwame, Wezena, Cletus A., Ocloo, Augustine
• Format: Journal Article
• Language: English
• Published: London BioMed Central 04.01.2022; BioMed Central Ltd; BMC
• Subjects: Affinity; Amides; Amidohydrolases - metabolism; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-inflammatory drugs; Arachidonamide; Arachidonic Acids - metabolism; Arachidonic Acids - pharmacology; Biomedical and Life Sciences; Biomedicine; Cannabinoids; Care and treatment; Chemical compounds; Cyclooxygenase-2; Drug discovery; Drugs; Enzyme Inhibitors - pharmacology; Enzyme kinetics; Enzymes; FAAH-1; Fatty Acids; Fatty-acid amide hydrolase; Glycerol; Health aspects; Humans; Hydrolase; Hydrolases; Hydrolysis; Indomethacin; Inflammation; Inhibitors; Liver; Meclofenamate; Metabolism; Nonsteroidal anti-inflammatory drugs; Oleamide; Pain; Pharmacology; Pharmacology/Toxicology; Physiological aspects; Polyunsaturated Alkamides - metabolism; Potassium; Proteins; Rankings; Rats; Side effects; Substrate inhibition; Substrate preferences; Substrates; Sulindac; Toxicity; United Kingdom > UK; United States > US; Germany; Hydrolysis; FAAH-1; Arachidonamide; NSAIDs; Oleamide; Mode; Affinity; Stearoylamide; Inhibition
• ISSN: 2050-6511; 2050-6511
• DOI: 10.1186/s40360-021-00539-1

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 V max 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. Conclusion Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.