Abstract
Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against the serine hydrolase superfamily ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amidohydrolases / antagonists & inhibitors*
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Amidohydrolases / chemistry
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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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COS Cells
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Chlorocebus aethiops
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Humans
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Ketones / chemical synthesis*
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Ketones / chemistry
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Ketones / pharmacology
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Models, Molecular
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Oxazoles / chemical synthesis*
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Oxazoles / chemistry
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Oxazoles / pharmacology
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Proteomics
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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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Recombinant Proteins / antagonists & inhibitors
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Serine Endopeptidases / chemistry
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Structure-Activity Relationship
Substances
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Analgesics
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Ketones
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Oxazoles
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Pyridines
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Recombinant Proteins
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Serine Endopeptidases
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Amidohydrolases
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fatty-acid amide hydrolase