EXCITATORY AMINO-ACID RECEPTOR ANTAGONISTS - RESOLUTION, ABSOLUTE STEREOCHEMISTRY, AND PHARMACOLOGY OF MINO-2-(5-TERT-BUTYL-3-HYDROXYISOXAZOL-4-YL)ACETIC AND MINO-2-(5-TERT-BUTYL-3-HYDROXYISOXAZOL-4-YL)ACETIC ACID (ATAA)

We have previously shown that S)-2-amino-2-(5-tert-butyl-3-hydroxyisox azol-4-yl) acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propi onic acid (AMPA) receptors. We have now resolved ATAA via diastereomer ic salt formation using N-BOC protected ATAA and (R)- and (S)-phenylet hylamine. Enantiomeric purities tee > 98%) of (R)- and (S)-ATAA were d etermined using the Crownpak CR(-) and CR(+) columns, respectively. Th e absolute configuration of (R)-ATAA was established by an X-ray cryst allographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATA A. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 mu M) the receptor binding of tritiated AMPA, kainic acid, or (RS )-3-(2-carboxypiperazin-4-yl) propyl-l-phosphonic acid, the latter bei ng a competitive NMDA antagonist. Electrophysiological experiments, us ing the rat cortical wedge preparation, showed the NMDA antagonist eff ect as well as the AMPA antagonist effect of ATAA to reside exclusivel y in the (R)-enantiomer (K-i = 75 +/- 5 mu M and 57 +/- 1 mu M, respec tively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-i nduced excitation (K-i > 1,000 mu M). (C) 1997 Wiley-Liss, Inc.