A binding site for nonsteroidal anti-inflammatory drugs in fatty acid amide hydrolase

J Am Chem Soc. 2013 Jan 9;135(1):22-5. doi: 10.1021/ja308733u. Epub 2012 Dec 21.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Carbazoles
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • carprofen