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

The activity of the amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist, -butyl-3-(phosphonomethoxy)-4-isoxaz olyl]propionic acid (ATPO), at recombinant ionotropic glutamate recept ors (GluRs) was evaluated using electrophysiological techniques, Respo nses at home-or heterooligomeric AMPA-preferring GluRs expressed in hu man embryonic kidney (HEK) 293 cells (GluR1-flip) or Xenopus laevis oo cytes (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 mu M. A Schild analysis for kainate (KA)-activated GluR1 recep tors showed ATPO to have a K-B of 8.2 mu M and a slope of unity, indic ating competitive inhibition. The antagonism by ATPO at GluR1 was of s imilar magnitude at holding potentials between -100 mV and +20 mV. In contrast, ATPO (<300 mu M), does not inhibit responses to kainate at h omomeric GluR6 or heterooligomeric GluR6/KA2 expressed in HEK 293 cell s but activated GluR5 and GluR5/KA2 expressed in X. laevis oocytes. AT PO produced <15% inhibition at the maximal concentration (300 mu M) of current responses through NR1A + NR2B receptors expressed in X. laevi s oocytes. Thus, ATPO shows a unique pharmacological profile, being an antagonist at GluR1-4 and a weak partial agonist at GIuR5 and GluR5/K A2.