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

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-ami no-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 [H-3]-(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 o f the endogenous ligand (S)-glutamic acid. (S)-TDPA thus represents a new s tructural class of EAAT2 inhibitor that will serve as a lead for the design of EAAT selective inhibitors. (C) 2000 Elsevier Science B.V. All rights re served.