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

Mikko J. Myllymaki, Heikki Kasnanen, Antti O. Kataja, Maija Lahtela-Kakkonen, Susanna M. Saario, Antti Poso, Ari M.P. Koskinen

    Research output: Contribution to journalArticleScientificpeer-review

    19 Citations (Scopus)
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    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.
    Original languageEnglish
    Pages (from-to)4179-4191
    JournalEUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
    Volume44
    Issue number10
    DOIs
    Publication statusPublished - 2009
    MoE publication typeA1 Journal article-refereed

    Keywords

    • FAAH inhibitor
    • fatty acid amide hydrolase (FAAH)
    • carbamate
    • enantiomeric pair

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