Document Detail


Sulfonyl fluoride inhibitors of fatty acid amide hydrolase.
MedLine Citation:
PMID:  23083016     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Sulfonyl fluorides are known to inhibit esterases. Early work from our laboratory has identified hexadecyl sulfonylfluoride (AM374) as a potent in vitro and in vivo inhibitor of fatty acid amide hydrolase (FAAH). We now report on later generation sulfonyl fluoride analogs that exhibit potent and selective inhibition of FAAH. Using recombinant rat and human FAAH, we show that 5-(4-hydroxyphenyl)pentanesulfonyl fluoride (AM3506) has similar inhibitory activity for both the rat and the human enzyme, while rapid dilution assays and mass spectrometry analysis suggest that the compound is a covalent modifier for FAAH and inhibits its action in an irreversible manner. Our SAR results are highlighted by molecular docking of key analogs.
Authors:
Shakiru O Alapafuja; Spyros P Nikas; Indu T Bharathan; Vidyanand G Shukla; Mahmoud L Nasr; Anna L Bowman; Nikolai Zvonok; Jing Li; Xiaomeng Shi; John R Engen; Alexandros Makriyannis
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-11-02
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  55     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-26     Completed Date:  2013-02-05     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10074-89     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Alkanesulfonates / pharmacology*
Amidohydrolases / antagonists & inhibitors*,  metabolism
Animals
Brain / drug effects*,  metabolism
Humans
Male
Mice
Models, Molecular
Molecular Structure
Palmitates / pharmacology*
Phenols / pharmacology*
Radioligand Assay
Rats
Recombinant Proteins / antagonists & inhibitors*,  metabolism
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
DA003801/DA/NIDA NIH HHS; DA007215/DA/NIDA NIH HHS; DA009158/DA/NIDA NIH HHS; R01 DA007215/DA/NIDA NIH HHS; R01 GM086507/GM/NIGMS NIH HHS; R01 GM101135/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/AM 3506; 0/AM 374; 0/Alkanesulfonates; 0/Palmitates; 0/Phenols; 0/Recombinant Proteins; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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