4(R)-(3-Phenylpropyl)-2(S)-glutamic acid, C((3)), is a synthetic analogue of L-glutamate. This analogue reversibly inhibits the membrane depolarization of neurons in the CA1 region of rat hippocampal slices evoked by N-methyl-D-aspartate (NMDA), with an EC50 value of 3.6 μM, whereas the depolarization of these neurons evoked by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid is not inhibited by C((3)). Analyses of the inhibitory effect of C((3)) on NMDA-evoked currents of dissociated rat hippocampal neurons further revealed that C((3)) acts as a competitive antagonist of NMDA receptors and that the inhibitory action of C((3)) is not use-dependent. Using goldfish retina as a model, we found that the neuronal damage produced by glutamate or by NMDA. was effectively prevented by C((3)). Incubation of retinas with high concentrations of C((3)), up to 1 mM, did not induce pathomorphological changes in retinal neurons. These results suggest that C((3)) is a useful neuroprotectant against excitotoxic damage of neurons.
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