title: A new structural class of subtype-selective inhibitor of cloned excitatory amino acid transporter, EAAT2.
abstract: We have studied the pharmacological effects of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and the enantiomers of (RS)-2-amino-3-(3-hydroxy-1,2, 5-thiadiazol-4-yl)propionic acid (TDPA) on cloned human excitatory amino acid transporter subtypes 1, 2 and 3 (EAAT1-3) expressed in Cos-7 cells. Whereas AMPA and (R)-TDPA were both inactive as inhibitors of [3H]-(R)-aspartic acid uptake on all three EAAT subtypes, (S)-TDPA was shown to selectively inhibit uptake by EAAT2 with a potency equal to that of the endogenous ligand (S)-glutamic acid. (S)-TDPA thus represents a new structural class of EAAT2 inhibitor that will serve as a lead for the design of EAAT selective inhibitors.
authors.affiliation: NeuroScience PharmaBiotec Research Center, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, 2 Universitetsparken, DK-2100, Copenhagen, Denmark. hbo@dfh.dk
authors.forename: H
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: M B
authors.initials: MB
authors.lastname: Hermit
authors.forename: B
authors.initials: B
authors.lastname: Nielsen
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: T N
authors.initials: TN
authors.lastname: Johansen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D027322:Amino Acid Transport System X-AG; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004274:DNA, Recombinant / Q000235:genetics; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D027322:Amino Acid Transport System X-AG; D002352:Carrier Proteins; D004274:DNA, Recombinant; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; D017981:Receptors, Neurotransmitter; D027981:Symporters; D014316:Tritium; D001224:Aspartic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid