Abstract
A class of bisarylimidazole derivatives are identified as potent inhibitors of the enzyme fatty acid amide hydrolase (FAAH). Compound 17 (IC(50)=2 nM) dose-dependently (0.1-10mg/kg, iv) potentiates the effects of exogenous anandamide (1 mg/kg, iv) in a rat thermal escape test (Hargreaves test), and shows robust antinociceptive activity in animal models of persistent (formalin test) and neuropathic (Chung model) pain. Compound 17 (20 mg/kg, iv) demonstrates activity in the formalin test that is comparable to morphine (3mg/kg, iv), and is dose-dependently inhibited by the CB1 antagonist SR141716A. In the Chung model, compound 17 shows antineuropathic effects similar to high-dose (100 mg/kg) gabapentin. FAAH inhibition shows potential utility for the clinical treatment of persistent and neuropathic pain.
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amines / pharmacology
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Analgesics / administration & dosage
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Analgesics / pharmacology*
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Animals
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Cyclohexanecarboxylic Acids / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology*
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Gabapentin
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Humans
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Mice
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Mice, Knockout
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Morphine / pharmacology
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Pain Measurement / drug effects*
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Pain Measurement / methods
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Piperidines / antagonists & inhibitors
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Piperidines / metabolism
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Pyrazoles / antagonists & inhibitors
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Pyrazoles / metabolism
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Rats
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / metabolism
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Rimonabant
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gamma-Aminobutyric Acid / pharmacology
Substances
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Amines
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Analgesics
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Cyclohexanecarboxylic Acids
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Enzyme Inhibitors
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Imidazoles
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Piperidines
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Pyrazoles
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Receptor, Cannabinoid, CB1
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gamma-Aminobutyric Acid
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Gabapentin
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Morphine
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Amidohydrolases
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fatty-acid amide hydrolase
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Rimonabant