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)

Abstract

We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3hydroxyisoxazol-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 µM) 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 µM and 57 ± 1 µM, respectively). Neither (R)-nor (S)-ATAA significantly reduced kainic acid-induced excitation (K i > 1,000 µM). Chirality 9: 529-536, 1997.

Ligands for Glutamate Receptors: Design and Therapeutic Prospects

“…139 Within the group of AMPA antagonists having "agonist chain lengths", the (R)-form is generally the active enantiomer, as exemplified by (R)-APPA, 123 (R)-2-Py-AMPA (78), 126 and (R)-ATAA (79). 140 These antagonists are remarkable because, despite their "agonist-like" structure and AMPA antagonist activity, they show very low receptor affinity in the [ 3 H]AMPA binding assay.…”

Inhibitors of AMPA and Kainate Receptors

“…Within the series of AMPA analogues, resolution of racemates has afforded a group of AMPA receptor antagonists with approximately equal potencies. These compounds all have "agonist like" structure, but the R-forms show competitive antagonist properties, whereas the S-forms are agonists [61,[76][77][78]. Like (R)-APPA, which was mentioned in the previous section, compounds such as (R)-2-Py-AMPA [76] and (R)-ATAA [77] are AMPA antagonists.…”

“…These compounds all have "agonist like" structure, but the R-forms show competitive antagonist properties, whereas the S-forms are agonists [61,[76][77][78]. Like (R)-APPA, which was mentioned in the previous section, compounds such as (R)-2-Py-AMPA [76] and (R)-ATAA [77] are AMPA antagonists. The pharmacology of this type of antagonists is remarkable because, in spite of their "agonist-like" structure and AMPA antagonist activity, they show very low receptor affinity in the [ 3 H]AMPA and [ 3 H]CNQX (see below) binding assays.…”

Excitatory amino acids

“…29 The same group has also synthesised using the same alkylation strategy outlined above, a range of biaryl-type AMPA analogues 32 in which the isoxazole methyl group of AMPA is replaced by a variety of aromatic or five or six-membered heterocyclic rings; some of these analogues were resolved and their absolute configuration established. [30][31][32] These substitutions generally led to a reduction in agonist activity at the AMPA receptor, although some 33 were active; the furyl derivative 32 (R = 2-furyl) was a potent agonist (IC 50 = 0.15 mM), and may find application as a photoaffinity label for the AMPA receptor. 34 These compounds did not show significant activity at the KA receptor.…”