Synthesis and single cell pharmacology of potential heterocyclic bioisosteres of the excitatory amino acid antagonist glutamic acid diethyl ester.

Article date: 1990/1/1

PubMed ID: 2206704

Journal name: Acta chemica Scandinavica (Copenhagen, Denmark : 1989) (ISSN: 0904-213X)


A series of heterocyclic analogues of glutamic acid diethyl ester (GDEE), an antagonist at central excitatory amino acid receptors, have been synthesized and tested biologically. (RS)-Ethyl alpha-amino-alpha-(3-ethoxyisoxazol-5-yl)acetate (7), (RS)-ethyl 2-amino-3-(3-ethoxy-5-methylisoxazol-4-yl)propionate (16) and closely related analogues were synthesized. Compound 7, a diethyl derivative of the naturally occurring excitatory amino acid ibotenic acid (IBO), was synthesized from 3-hydroxy-5-methylisoxazole (1) via 3-ethoxyisoxazol-5-ylacetic acid (5) and its ethyl ester. Nitrosation of this ester followed by catalytic reduction gave 7. The ethyl ester of IBO, 9, was synthesized in a similar manner from 3-benzyloxyisoxazol-5-ylacetic acid (8). Ethyl derivatives of the synthetic excitatory amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) were synthesized from 3-hydroxy-4,5-dimethylisoxazole (10) through a diethyl acetylaminomalonate derivative, which upon deprotection gave the 3-ethoxy derivative of AMPA (15). Esterification of 15 gave the diethyl derivative 16 and the ethyl ester of AMPA (18) as well as N-ethylated derivatives of AMPA, 21 and 22 were synthesized. The final products were tested microelectrophoretically. The derivatives 7, 9, 15, 16 and 18 were weak and non-selective excitatory amino acid antagonists, whereas 21 and 22 were found to be inactive.

Author List: Madsen U, Nielsen E O, Curtis D R, Beattie D T, Krogsgaard-Larsen P

Publication Types: Journal Article; Research Support, Non-U.S. Gov't

Substances mentioned in the article: Excitatory Amino Acid Antagonists; Glutamates; Heterocyclic Compounds; glutamic acid diethyl ester;

Mesh terms: Action Potentials/drug effects; Animals; Cats; Chemical Phenomena; Chemistry; Excitatory Amino Acid Antagonists; Glutamates/chemical synthesis; Heterocyclic Compounds; Interneurons/drug effects; Molecular Structure; Spinal Cord/cytology;

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