RESOLUTION, ABSOLUTE STEREOCHEMISTRY, AND PHARMACOLOGY OF THE S-(-ISOMERS AND R-(-)-ISOMERS OF THE APPARENT PARTIAL AMPA RECEPTOR AGONIST AMINO-3-(3-HYDROXY-5-PHENYLISOXAZOL-4-YL)PROPIONIC ACID [(R,S)-APPA]())

Amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid ((R,S)-APPA) i s the only partial agonist at the amino-3-(3-hydroxy-5-methylisoxazol- 4-yl)propionic acid (AMPA) subtype of excitatory amino acid receptors so far described. In light of the pharmacological interest in partial agonists, we have now accomplished the resolution of(R,S)-APPA. (S)-()-APPA (5) and (R)-(-)-APPA (6) were obtained in high enantiomeric pur ity using (R)-(+)- and (S)-(-)-1-phenylethylamine, respectively, as re solving agents. The absolute stereochemistry,ry of 6 was established b y X-ray analysis of 6.HCl.0.25H(2)O. Compounds 5 and 6 were tested ele ctropharmacologically using the rat cortical wedge preparation and in receptor-binding assays using [H-3]- AMPA, [H-3]kainic acid, and the N -methyl-D-aspartic acid (NMDA) receptor ligands [H-3]CPP, [H-3]MK-801, and [H-3]glycine. Whereas 6 did not significantly affect the binding of any of these ligands (IC50 > 100 mu M), compound 5 revealed affinit y for only the [H-3]AMPA-binding site (IC50 = 6 mu M). In electropharm acological tests, 5 showed full AMPA receptor agonism (EC(50) = 230 mu M). This effect of 5 was insensitive to the NMDA antagonist CPP but w as inhibited competitively by the non-NMDA antagonist NBQX (pK(i) = 6. 30). Compound 6, on the other hand, turned out to be a non-NMDA recept or antagonist, inhibiting competitively depolarizations induced by AMP A (pK(i) = 3.54), kainic acid (pK(i) = 3.07), and 5 (pK(i) = 3.57).