title: 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.
abstract: 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.
authors.affiliation: Departement de Chimie, Universite Blaise Pascal, 63177 Aubiere Cedex, France.
authors.forename: Emanuelle
authors.initials: E
authors.lastname: Sagot
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.forename: Darryl S
authors.initials: DS
authors.lastname: Pickering
authors.forename: Xiaosui
authors.initials: X
authors.lastname: Pu
authors.forename: Michelle
authors.initials: M
authors.lastname: Umberti
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Assaf
authors.forename: Bétina
authors.initials: B
authors.lastname: Aboab
authors.forename: Jean
authors.initials: J
authors.lastname: Bolte
authors.forename: Thierry
authors.initials: T
authors.lastname: Gefflaut
authors.forename: Lennart
authors.initials: L
authors.lastname: Bunch
mesh_terms: D002460:Cell Line; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D005977:Glutarates / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008564:Membrane Potentials / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
chemical_list: C530997:2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D005977:Glutarates; C493397:SLC1A2 protein, human