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

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A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
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Date
2009
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Mcode
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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.
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Keywords
FAAH inhibitor, fatty acid amide hydrolase (FAAH), carbamate, enantiomeric pair
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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