Molecular pharmacology of the AMPA agonist, (S)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(S)-APPA] and the AMPA antagonist, (R)-APPA

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Abstract

The heterocyclic analogue of (S)-glutamic acid, (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [(S)-AMPA] is a potent and selective AMPA receptor agonist, whereas the enantiomeric compound, (R)-AMPA, is virtually inactive. We have previously characterized (RS)-2-amino-3-(3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(RS)-APPA] as a partial AMPA receptor agonist showing about 60% of the efficacy of (RS)-AMPA. This partial agonism produced by (RS)-APPA is, however, only apparent, since resolution of (RS)-APPA has now been shown to provide the full AMPA receptor agonist, (S)-APPA, whereas (R)-APPA is a non-N-methyl-D-aspartic acid (non-NMDA) receptor antagonist showing preferential AMPA blocking effects. In agreement with classical theories for competitive interaction between agonists and antagonists, the efficacy of depolarizations produced by (S)-APPA in the rat cortical wedge preparation was shown to be progressively reduced with increasing molar ratios of (R)-APPA/(S)-APPA. These compounds and the competitive antagonists (RS)-2-amino-3-(3-carboxymethoxy-5-methyl-4-isoxazolyl)propionic acid [(RS)-AMOA], 6-cyano-7-nitroquinoxalin-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo(f)quinoxalin-2,3-dione (NBQX) were also tested in [3H]AMPA and [3H]CNQX binding systems, the latter ligand being used in the absence or presence of thiocyanate ions. On the basis of these studies it is suggested that (RS)-AMPA and the AMPA agonist (S)-APPA interact with a high-affinity receptor conformation, whereas the competitive antagonists (RS)-AMOA and (R)-APPA, derived from these agonists, preferentially bind to a low-affinity AMPA receptor conformation.(ABSTRACT TRUNCATED AT 250 WORDS)
Original languageEnglish
JournalNeurochemistry International
Volume24
Issue number6
Pages (from-to)507-15
Number of pages9
ISSN0197-0186
Publication statusPublished - Jun 1994

Keywords

  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Alanine
  • Animals
  • Brain
  • Cell Membrane
  • Cerebral Cortex
  • Evoked Potentials
  • Isoxazoles
  • Male
  • Organ Specificity
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, AMPA
  • Stereoisomerism
  • Structure-Activity Relationship
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

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