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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP-Binding Cassette Transporters / antagonists & inhibitors
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Amino Acid Transport System X-AG
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Animals
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Aspartic Acid / chemistry
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Aspartic Acid / drug effects
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Aspartic Acid / metabolism
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Biological Transport / drug effects
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COS Cells
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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DNA, Recombinant / genetics
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Excitatory Amino Acid Transporter 2
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Glutamate Plasma Membrane Transport Proteins
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Receptors, Neurotransmitter / antagonists & inhibitors*
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Receptors, Neurotransmitter / genetics
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Receptors, Neurotransmitter / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Symporters*
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Tritium
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemistry
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology*
Substances
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ATP-Binding Cassette Transporters
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Amino Acid Transport System X-AG
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Carrier Proteins
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DNA, Recombinant
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Excitatory Amino Acid Transporter 2
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Glutamate Plasma Membrane Transport Proteins
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Receptors, Neurotransmitter
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Symporters
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Tritium
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Aspartic Acid
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid