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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.
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
November 1992,
Journal of neurochemistry,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
March 1997,
Neurochemical research,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
June 1990,
Neuroscience letters,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
March 1979,
Biochimica et biophysica acta,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
January 1989,
Clinical physiology and biochemistry,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
August 1989,
European journal of pharmacology,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
April 1995,
European journal of pharmacology,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
March 2000,
Pharmaceutica acta Helvetiae,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
January 1981,
Progress in clinical and biological research,
D D Schoepp, and
B G Johnson, and
E C Smith, and
L A McQuaid
September 1994,
Nihon yakurigaku zasshi. Folia pharmacologica Japonica,
