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

Research output: Contribution to journalJournal articleResearchpeer-review

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

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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume51
Issue number14
Pages (from-to)4085-4092
Number of pages8
ISSN0022-2623
DOIs
Publication statusPublished - 2008

    Research areas

  • Cell Line, Excitatory Amino Acid Antagonists, Glutamate Plasma Membrane Transport Proteins, Glutarates, Humans, Magnetic Resonance Spectroscopy, Membrane Potentials, Spectrometry, Mass, Electrospray Ionization, Stereoisomerism

ID: 5345305