ANTAGONIST PROPERTIES OF A PHOSPHONO ISOXAZOLE AMINO ACID AT GLUTAMATE R1-4 (R, S)-2-AMINO-3-(3-HYDROXY-5-METHYL-4-ISOXAZOLYL)PROPIONIC ACID RECEPTOR SUBTYPES

The activity of the ( R,S )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist, ( R,S )-2-amino-3-[5- tert -butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO), at recombinant ionotropic glutamate receptors (GluRs) was evaluated using electrophysiological techniques. Responses at homo- or heterooligomeric AMPA-preferring GluRs expressed in human embryonic kidney (HEK) 293 cells (GluR1-flip) or Xenopus laevis oocytes (GluR1–4-flop or GluR1-flop + GluR2) were potently inhibited by ATPO with apparent dissociation constants ( K b values) ranging from 3.9 to 26 μm. A Schild analysis for kainate (KA)-activated GluR1 receptors showed ATPO to have a K B of 8.2 μmand a slope of unity, indicating competitive inhibition. The antagonism by ATPO at GluR1 was of similar magnitude at holding potentials between −100 mV and +20 mV. In contrast, ATPO ( X. laevis oocytes. ATPO produced X. laevis oocytes. Thus, ATPO shows a unique pharmacological profile, being an antagonist at GluR1–4 and a weak partial agonist at GluR5 and GluR5/KA2.