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)

TY - JOUR

T1 - Excitatory amino acid receptor antagonists

T2 - resolution, absolute stereochemistry, and pharmacology of (S)- and (R)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA)

AU - Johansen, T N

AU - Frydenvang, Karla Andrea

AU - Ebert, B

AU - Madsen, U

AU - Krogsgaard-Larsen, P

PY - 1997

Y1 - 1997

N2 - 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).

AB - 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).

KW - Animals

KW - Binding, Competitive

KW - Cerebral Cortex

KW - Corpus Callosum

KW - Crystallography, X-Ray

KW - Electrophysiology

KW - Excitatory Amino Acid Antagonists

KW - Indicators and Reagents

KW - Isoxazoles

KW - Kainic Acid

KW - Models, Molecular

KW - Molecular Conformation

KW - Molecular Structure

KW - Radioligand Assay

KW - Rats

KW - Receptors, AMPA

KW - Receptors, N-Methyl-D-Aspartate

KW - Stereoisomerism

KW - Tritium

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

U2 - 10.1002/(SICI)1520-636X(1997)9:5/6<529::AID-CHIR20>3.0.CO;2-P

DO - 10.1002/(SICI)1520-636X(1997)9:5/6<529::AID-CHIR20>3.0.CO;2-P

M3 - Journal article

C2 - 9329180

SN - 0899-0042

VL - 9

SP - 529

EP - 536

JO - Chirality

JF - Chirality

IS - 5-6

ER -