Document Detail

Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human excitatory amino acid transporter subtype 2.
MedLine Citation:
PMID:  18578477     Owner:  NLM     Status:  MEDLINE    
In the mammalian central nervous system (CNS), the action of sodium dependent excitatory amino acid transporters (EAATs) is responsible for termination of glutamatergic neurotransmission by reuptake of ( S) -glutamate (Glu) from the synaptic cleft. Five EAAT subtypes have been identified, of which EAAT1-4 are present in the CNS, while EAAT5 is localized exclusively in the retina. In this study, we have used an enantioselective chemo-enzymatic strategy to synthesize 10 new Glu analogues 2a- k ( 2d is exempt) with different functionalities in the 4 R-position and characterized their pharmacological properties at the human EAAT1-3. In particular, one compound, 2k, displayed a significant preference as inhibitor of the EAAT2 subtype over EAAT1,3. The compound also displayed very low affinities toward ionotropic and metabotropic Glu receptors, making it the most selective EAAT2 inhibitor described so far.
Emanuelle Sagot; Anders A Jensen; Darryl S Pickering; Xiaosui Pu; Michelle Umberti; Tine B Stensbøl; Birgitte Nielsen; Zeinab Assaf; Bétina Aboab; Jean Bolte; Thierry Gefflaut; Lennart Bunch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-06-25
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  51     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-07-22     Completed Date:  2008-08-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4085-92     Citation Subset:  IM    
Departement de Chimie, Universite Blaise Pascal, 63177 Aubiere Cedex, France.
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MeSH Terms
Cell Line
Excitatory Amino Acid Antagonists / chemical synthesis*,  pharmacology*
Glutamate Plasma Membrane Transport Proteins / antagonists & inhibitors*
Glutarates / chemical synthesis*,  pharmacology*
Magnetic Resonance Spectroscopy
Membrane Potentials / drug effects
Spectrometry, Mass, Electrospray Ionization
Reg. No./Substance:
0/2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid; 0/Excitatory Amino Acid Antagonists; 0/Glutamate Plasma Membrane Transport Proteins; 0/Glutarates; 0/SLC1A2 protein, human

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

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