Abstract
Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 microM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 microM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amidohydrolases / antagonists & inhibitors
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Amidohydrolases / metabolism*
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Analgesics / chemical synthesis*
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Arachidonic Acids / metabolism
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Benzoates / chemical synthesis*
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Benzoates / chemistry
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Benzoates / pharmacology
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Endocannabinoids
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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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Inhibitory Concentration 50
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Kinetics
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Magnetic Resonance Spectroscopy
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Polyunsaturated Alkamides / metabolism
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Spectrophotometry, Infrared
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Structure-Activity Relationship
Substances
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Analgesics
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Anti-Inflammatory Agents, Non-Steroidal
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Arachidonic Acids
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Benzoates
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Endocannabinoids
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Enzyme Inhibitors
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Polyunsaturated Alkamides
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Pyridines
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Amidohydrolases
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fatty-acid amide hydrolase
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anandamide