Format

Send to

Choose Destination
See comment in PubMed Commons below
Chem Biol. 2009 Apr 24;16(4):411-20. doi: 10.1016/j.chembiol.2009.02.013.

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

Author information

1
Pfizer Global Research and Development, Groton, CT 06340, USA. kay.ahn@pfizer.com

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.

PMID:
19389627
PMCID:
PMC2692831
DOI:
10.1016/j.chembiol.2009.02.013
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center