Abstract
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 laevisoocytes (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 aK 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 (<300 μm), does not inhibit responses to kainate at homomeric GluR6 or heterooligomeric GluR6/KA2 expressed in HEK 293 cells but activated GluR5 and GluR5/KA2 expressed in X. laevis oocytes. ATPO produced <15% inhibition at the maximal concentration (300 μm) of current responses through NR1A + NR2B receptors expressed in 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.
Footnotes
- Received July 18, 1997.
- Accepted November 5, 1997.
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Send reprint requests to: Philip Wahl, Ph.D., Department of Molecular Pharmacology, Novo Nordisk A/S, Novo Nordisk Park, DK 2760 Maaloev, Denmark. E-mail: pwa{at}novo.dk
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This work was supported by grants from the European Economic Community (BIO2-CT93-0243) and the John Merck Fund.
- The American Society for Pharmacology and Experimental Therapeutics
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