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A novel glutamate agonist, TAN-950 A, isolated from streptomycetes.

Authors
  • Iwama, T1
  • Nagai, Y
  • Tamura, N
  • Harada, S
  • Nagaoka, A
  • 1 Biology Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan. , (Japan)
Type
Published Article
Journal
European Journal of Pharmacology
Publisher
Elsevier
Publication Date
May 17, 1991
Volume
197
Issue
2-3
Pages
187–192
Identifiers
PMID: 1680709
Source
Medline
License
Unknown

Abstract

A novel antifungal amino acid antibiotic, TAN-950 A ([S]-2-amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl)propanoic acid), was found to have affinity for three excitatory amino acid (EAA) receptors and to inhibit [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA), [3H]kainate and [3H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid ([3H]CPP) binding competitively. It caused excitation of rat hippocampal CA1 neurons in vitro, an effect that was antagonized by an AMPA/kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX). Chemical modification of TAN-950 A brought about a large change in its pharmacological activity. Alkylation at the C-3 position of the isoxazolone ring markedly increased the ability to elicite neuronal firing. This agonistic effect was also antagonized by DNQX. The (R) enantiomer of TAN-950 A had increased selectivity for the N-methyl-D-aspartate (NMDA) receptor subtype. This selectivity was further enhanced by removal of the methylene group from the amino acid moiety. The most potent NMDA agonistic activity was observed with [R]-2-amino-2-(2,5-dihydro-3-methyl-5-oxo-4-isoxazolyl)acetic acid. These derivatives of TAN-950 A might be useful agents for investigating the pharmacological and physiological roles of EAA receptors.

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