2166902

Stereoselectivity and mode of inhibition of phosphoinositide-coupled excitatory amino acid receptors by 2-amino-3-phosphonopropionic acid.

Article date: 1990/8/1

PubMed ID: 2166902

Journal name: Molecular pharmacology (ISSN: 0026-895X)

ABSTRACT

DL-2-Amino-3-phosphonopropionic acid, a phosphonate-substituted derivative of aspartic acid, has been shown to be an inhibitor of excitatory amino acid-stimulated phosphoinositide hydrolysis in rat brain slices. In this study, the enantiomers of 2-amino-3-phosphonopropionic acid were synthesized and used to further characterize the stereoselectivity and mechanism of interaction of this compound for inhibiting phosphoinositide-coupled (metabotropic) excitatory amino acid receptors. L-2-Amino-3-phosphonopropionic acid was 3-5 times more potent than D-2-amino-3-phosphonopropionic acid as an inhibitor of ibotenate-stimulated [3H]inositol monophosphate formation in slices of the rat hippocampus or quisqualate-stimulated [3H]inositol monophosphate formation in neonatal rat cerebral cortical slices. Carbachol-stimulated phosphoinositide hydrolysis was not inhibited by L-2-amino-3-phosphonopropionic acid, and L-2-amino-3-phosphonopropionic acid had no appreciable affinity for ionotropic excitatory amino acid receptors at concentrations required to inhibit metabotropic excitatory amino acid responses. The inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid on phosphoinositide hydrolysis were not competitive, because they could not be surmounted by increasing concentrations of ibotenate or quisqualate. L-2-Amino-3-phosphonopropionic acid inhibition also could not be prevented by washing the tissue before incubation with ibotenate. Thus, L-2-amino-3-phosphonopropionic acid is a stereoselective inhibitor of metabotropic excitatory amino acid receptors with little affinity for ionotropic receptors. However, the inhibitory effects of L-2-amino-3-phosphonopropionic acid or L-2-amino-4-phosphonobutyric acid were not readily reversed, and the site at which they act to inhibit metabotropic excitatory amino acid receptors remains to be determined.

Author List: Schoepp D D, Johnson B G, Smith E C, McQuaid L A

Publication Types: Comparative Study; Journal Article

Substances mentioned in the article: Aminobutyrates; Inositol Phosphates; Pipecolic Acids; Piperidines; Receptors, Amino Acid; Receptors, Cell Surface; 2-amino-3-phosphonopropionic acid; Ibotenic Acid; Aspartic Acid; selfotel; N-Methylaspartate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; 2-amino-4-phosphonobutyric acid; Alanine; Kainic Acid;

Mesh terms: Alanine/analogs & derivatives; Aminobutyrates/pharmacology; Animals; Aspartic Acid/analogs & derivatives; Brain/drug effects; Hydrolysis/drug effects; Ibotenic Acid/analogs & derivatives; Inositol Phosphates/metabolism; Kainic Acid/pharmacology; Male; N-Methylaspartate; Pipecolic Acids; Piperidines/pharmacology; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface/drug effects; Stereoisomerism; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;

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