A new structural class of subtype-selective inhibitor of cloned excitatory amino acid transporter, EAAT2

TY - JOUR

T1 - A new structural class of subtype-selective inhibitor of cloned excitatory amino acid transporter, EAAT2

AU - Bräuner-Osborne, Hans

AU - Hermit, M B

AU - Nielsen, B

AU - Krogsgaard-Larsen, P

AU - Johansen, T N

PY - 2000/10/6

Y1 - 2000/10/6

N2 - 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.

AB - 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.

KW - ATP-Binding Cassette Transporters

KW - Amino Acid Transport System X-AG

KW - Animals

KW - Aspartic Acid

KW - Biological Transport

KW - COS Cells

KW - Carrier Proteins

KW - DNA, Recombinant

KW - Excitatory Amino Acid Transporter 2

KW - Glutamate Plasma Membrane Transport Proteins

KW - Receptors, Neurotransmitter

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Symporters

KW - Tritium

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

M3 - Journal article

C2 - 11011030

SN - 0014-2999

VL - 406

SP - 41

EP - 44

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

IS - 1

ER -