Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields

Eur J Med Chem. 2009 Oct;44(10):4179-91. doi: 10.1016/j.ejmech.2009.05.012. Epub 2009 May 22.

Abstract

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are the main enzymes responsible for the hydrolysis of endogenous cannabinoids N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. Phenyl alkylcarbamates are FAAH inhibitors with anxiolytic and analgesic activities in vivo. Herein we present for the first time the synthesis and biological evaluation of a series of chiral 3-(2-oxazoline)-phenyl N-alkylcarbamates as FAAH inhibitors. Furthermore, the structural background of chirality on the FAAH inhibition is explored by analyzing the protein-ligand interactions. Remarkably, 10-fold difference in potency was observed for (R)- and (S)-derivatives of 3-(5-methyl-4,5-dihydrooxazol-2-yl)phenyl cyclohexylcarbamate (6a vs. 6b). Molecular modelling indicated an important interaction between the oxazoline nitrogen and FAAH active site.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / chemistry
  • Amidohydrolases / metabolism*
  • Animals
  • Brain / enzymology
  • Carbamates / chemical synthesis
  • Carbamates / chemistry*
  • Carbamates / pharmacology*
  • Humans
  • Male
  • Models, Molecular
  • Molecular Conformation
  • Monoacylglycerol Lipases / metabolism
  • Oxazoles / chemical synthesis
  • Oxazoles / chemistry*
  • Oxazoles / pharmacology*
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Carbamates
  • Oxazoles
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase