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

Loading...
Thumbnail Image
Journal Title
Journal ISSN
Volume Title
A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
This publication is imported from Aalto University research portal.
View publication in the Research portal
View/Open full text file from the Research portal
Date
2009
Major/Subject
Mcode
Degree programme
Language
en
Pages
4179-4191
Series
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, Volume 44, issue 10
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.
Description
Keywords
FAAH inhibitor, fatty acid amide hydrolase (FAAH), carbamate, enantiomeric pair
Other note
Citation
Myllymaki , M J , Kasnanen , H , Kataja , A O , Lahtela-Kakkonen , M , Saario , S M , Poso , A & Koskinen , A M P 2009 , ' Chiral 3-(4,5-dihydrooxazol-2-yl)phenyl alkylcarbamates as novel FAAH inhibitors: Insight into FAAH enantioselectivity by molecular docking and interaction fields ' , EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY , vol. 44 , no. 10 , pp. 4179-4191 . https://doi.org/10.1016/j.ejmech.2009.05.012