MOLECULAR PHARMACOLOGY OF THE AMPA AGONIST, AMINO-3-(3-HYDROXY-5-PHENYL-4-ISOXAZOLYL)PROPIONIC ACID [(S)-APPA] AND THE AMPA ANTAGONIST, (R)-APPA

The heterocyclic analogue of (S)-glutamic acid, (S)-2-amino-3- (3-hydr oxy-5-methyl-4-isoxazolyl)propionic acid [(S)-AMPA] is a potent and se lective AMPA receptor agonist, whereas the enantiomeric compound, (R)- AMPA, is virtually inactive. We have previously characterized amino-3- (3-hydroxy-5-phenyl-4-isoxazolyl)propionic acid [(RS)-APPA] as a parti al AMPA receptor agonist showing about 60% of the efficacy of (RS)-AMP A. This partial agonism produced by (RS)-APPA is, however, only appare nt, since resolution of (RS)-APPA has now been shown to provide the fu ll AMPA receptor agonist, (S)-APPA, whereas (X)-APPA is a non-N-methyl -D-aspartic acid (non-NMDA) receptor antagonist showing preferential A MPA blocking effects. In agreement with classical theories for competi tive interaction between agonists and antagonists, the efficacy of dep olarizations produced by (S)-APPA in the rat cortical wedge preparatio n was shown to be progressively reduced with increasing molar ratios o f (R)APPA/(S)-APPA. These compounds and the competitive antagonists -( 3-carboxymelhoxy-5-methyl-4-isoxazoiyl)propionic acid [(RS)-AMOA], 6-c yano-7-nitroquinoxalin-2,3-dione (CNQX) and 6-nitro-7-sulfamoylbenzo(f )quinoxalin-2,3 (NBQX) were also tested in [H-3]AMPA and [H-3]CNQX bin ding systems, the latter ligand bring used in the absence or presence of thiocyanate ions. On the basis of these studies it is suggested tha t (RS)-AMPA and the AMPA agonist (S)-APPA interact with a high-affinit y receptor conformation, whereas the competitive antagonists (RS)-AMOA and (R)-APPA, derived from these agonists, preferentially bind to a l ow-affinity AMPA receptor conformation. The competitive antagonists, C NQX and NBQX which are structurally unrelated to (RS)-AMPA or (RS)-APP A, do not seem to discriminate between these two AMPA receptor conform ations. The modified [H-3]CNQX binding assay containing thiocyanate io ns was shown to provide receptor affinity data for AMPA receptor agoni sts as well as antagonists, which correlate with the potencies of thes e compounds in the cortical wedge preparation. Using autoradiographic techniques, (S)- and (R)-APPA were shown to exhibit significantly diff erent absolute potencies as inhibitors of [H-3]AMPA binding in a numbe r of regions of the rat brain.