A novel NMDA receptor antagonist protects against N-methyl-D-aspartate- and glutamate-induced neurotoxicity in the goldfish retina

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 EC(50) value of 3.6 mu M, whereas the depolarization of these neurons evoked by alpha-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.