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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)
Author(s) -
Johansen Tommy N.,
Frydenvang Karla,
Ebert Bjarke,
Madsen Ulf,
KrogsgaardLarsen Povl
Publication year - 1997
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1997)9:5/6<529::aid-chir20>3.0.co;2-p
Subject(s) - chemistry , kainic acid , stereochemistry , nmda receptor , ampa receptor , enantiomer , antagonist , glutamate receptor , receptor , biochemistry
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 (IC 50 > 100 μ M ) 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 ( K i = 75 ± 5 μ M and 57 ± 1 μ M, respectively). Neither (R)‐ nor (S)‐ATAA significantly reduced kainic acid‐induced excitation ( K i > 1,000 μ M ). Chirality 9:529–536, 1997. © 1997 Wiley‐Liss, Inc.