A Binding Site for Nonsteroidal Anti-inflammatory Drugs in Fatty Acid Amide Hydrolase

In addition to inhibiting the cyclooxygenase (COX)-mediated biosynthesis of prostanoids, various widely used nonsteroidal anti-inflammatory drugs (NSAIDs) enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH). The X-ray structure of...

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Veröffentlicht in:	Journal of the American Chemical Society 2013-01, Vol.135 (1), p.22-25
Hauptverfasser:	Bertolacci, Laura, Romeo, Elisa, Veronesi, Marina, Magotti, Paola, Albani, Clara, Dionisi, Mauro, Lambruschini, Chiara, Scarpelli, Rita, Cavalli, Andrea, De Vivo, Marco, Piomelli, Daniele, Garau, Gianpiero
Format:	Artikel
Sprache:	eng
Schlagworte:	Amidohydrolases - antagonists & inhibitors Amidohydrolases - metabolism Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Binding Sites - drug effects Carbazoles - chemistry Carbazoles - pharmacology Dose-Response Relationship, Drug Models, Molecular Molecular Structure Structure-Activity Relationship
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Zusammenfassung:	In addition to inhibiting the cyclooxygenase (COX)-mediated biosynthesis of prostanoids, various widely used nonsteroidal anti-inflammatory drugs (NSAIDs) enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH). The X-ray structure of FAAH in complex with the NSAID carprofen, along with site-directed mutagenesis, enzyme activity assays, and NMR analysis, has revealed the molecular details of this interaction, providing information that may guide the design of dual FAAH–COX inhibitors with superior analgesic efficacy.
ISSN:	0002-7863 1520-5126
DOI:	10.1021/ja308733u