Excitatory amino acid receptor antagonists: resolution, absolute stereochemistry, and pharmacology of (S)- and (R)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA).
We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-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)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation using N-BOC protected ATAA and (R)- and (S)-phenylethylamine. Enantiomeric purities (ee > 98%) of (R)- and (S)-ATAA were determined using the Crownpak CR(-) and CR(+) columns, respectively. The absolute configuration of (R)-ATAA was established by an X-ray crystallographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation (Ki > 1,000 microM).
Johansen
T N
TN
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Frydenvang
K
K
Ebert
B
B
Madsen
U
U
Krogsgaard-Larsen
P
P
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D003337:Corpus Callosum / Q000187:drug effects / Q000502:physiology; D018360:Crystallography, X-Ray; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D007608:Kainic Acid / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D007202:Indicators and Reagents; D007555:Isoxazoles; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid