N-Methyl-d-aspartic Acid Receptor Agonists: Resolution, Absolute Stereochemistry, and Pharmacology of the Enantiomers of 2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic Acid

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Abstract
(R,S)-2-Amino-2-(3-hydroxy-5-methyl-4-isoxazolyl)acetic acid [(R,S)-AMAA, 4] is a potent and selective agonist at the N-methyl-d-aspartic acid (NMDA) subtype of excitatory amino acid receptors. Using the Ugi “four-component condensation” method, the two diastereomers (2R)- and (2S)-2-[3-(benzyloxy)-5-methyl-4-isoxazolyl]-N-tert-butyl-2-[N-[(S)-1-phenylethyl]benzamido]acetamide (16 and 17, respectively) were synthesized and separated chromatographically. The absolute stereochemistry of 16 was confirmed by an X-ray analysis. Deprotection of these intermediates did, however, provide (R)- (8) and (S)- (9) AMAA, respectively, in extensively racemized forms. N-BOC-protected (R,S)-AMAA (21) was successfully resolved via diastereomeric salt formation using cinchonidine. The stereochemical purity and stability of 8 and 9 obtained via this resolution were determined using chiral HPLC. (R)-AMAA (8) showed weak affinity for [3H]AMPA receptor sites (IC50 = 72 ± 13 μM) and was shown to be a more potent inhibitor of [3H]CPP binding (IC50 = 3.7 ± 1.5 μM) than (S)-AMAA (9) (IC50 = 61 ± 6.4 μM). Neither enantiomer of AMAA affected [3H]kainic acid receptor binding significantly. In electrophysiological studies using rat brain tissue, 8 (EC50 = 7.3 ± 0.3 μM) was 1 order of magnitude more potent than 9 (EC50 = 75 ± 9 μM) as an NMDA receptor agonist.

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