Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain.

Abstract

Endocannabinoids are lipid signaling molecules that regulate a wide range of mammalian behaviors, including pain, inflammation, and cognitive/emotional state. The endocannabinoid anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH), and there is currently much interest in developing FAAH inhibitors to augment endocannabinoid signaling in vivo. Here, we report the discovery and detailed characterization of a highly efficacious and selective FAAH inhibitor, PF-3845. Mechanistic and structural studies confirm that PF-3845 is a covalent inhibitor that carbamylates FAAH's serine nucleophile. PF-3845 selectively inhibits FAAH in vivo, as determined by activity-based protein profiling; raises brain anandamide levels for up to 24 hr; and produces significant cannabinoid receptor-dependent reductions in inflammatory pain. These data thus designate PF-3845 as a valuable pharmacological tool for in vivo characterization of the endocannabinoid system.

• Authors: Kay Ahn, Douglas S Johnson, Mauro Mileni, David Beidler, Jonathan Z Long, Michele K McKinney, Eranthie Weerapana, Nalini Sadagopan, Marya Liimatta, Sarah E Smith, Scott Lazerwith, Cory Stiff, Satwik Kamtekar, Keshab Bhattacharya, Yanhua Zhang, Stephen Swaney, Keri Van Becelaere, Raymond C Stevens, Benjamin F Cravatt
• Journal: Chemistry & biology (Chem Biol) Vol. 16 Issue 4 Pg. 411-20 (Apr 24 2009) ISSN: 1879-1301 [Electronic] United States
• PMID: 19389627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Arachidonic Acids
• Endocannabinoids
• Enzyme Inhibitors
• Piperazines
• Piperidines
• Polyunsaturated Alkamides
• Receptors, Cannabinoid
• Piperazine
• piperidine
• Urea
• Amidohydrolases
• fatty-acid amide hydrolase
• anandamide

Topics

• Amidohydrolases (antagonists & inhibitors, chemistry, metabolism)
• Animals
• Arachidonic Acids (metabolism)
• Brain (metabolism)
• Crystallography, X-Ray
• Endocannabinoids
• Enzyme Inhibitors (chemical synthesis, chemistry, metabolism, therapeutic use)
• Humans
• Male
• Pain (chemically induced, drug therapy, immunology)
• Piperazine
• Piperazines (chemical synthesis, chemistry, metabolism)
• Piperidines (chemical synthesis, chemistry, metabolism)
• Polyunsaturated Alkamides (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Cannabinoid (metabolism)
• Structure-Activity Relationship
• Urea (chemical synthesis, chemistry, metabolism)