A novel glutamate agonist, TAN-950 A, isolated from streptomycetes.
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.
Iwama
T
T
Biology Research Laboratories, Takeda Chemical Industries, Ltd., Osaka, Japan.
Nagai
Y
Y
Tamura
N
N
Harada
S
S
Nagaoka
A
A
D000818:Animals; D000935:Antifungal Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D005971:Glutamates / Q000378:metabolism*; D018698:Glutamic Acid; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism; D013302:Streptomyces / Q000737:chemistry; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D005971:Glutamates; D018698:Glutamic Acid; D007555:Isoxazoles; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C071084:2-amino-3-(2,5-dihydro-5-oxo-4-isoxazolyl)propanoic acid