| 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. | |
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MedLine Citation:
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PMID: 18578477 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2008-06-25 |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 51 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2008 Jul |
Date Detail:
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Created Date: 2008-07-22 Completed Date: 2008-08-29 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 4085-92 Citation Subset: IM |
Affiliation:
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Departement de Chimie, Universite Blaise Pascal, 63177 Aubiere Cedex, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Line Excitatory Amino Acid Antagonists / chemical synthesis*, pharmacology* Glutamate Plasma Membrane Transport Proteins / antagonists & inhibitors* Glutarates / chemical synthesis*, pharmacology* Humans Magnetic Resonance Spectroscopy Membrane Potentials / drug effects Spectrometry, Mass, Electrospray Ionization Stereoisomerism |
| Chemical | |
Reg. No./Substance:
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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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