The electrophysiological effects of 4(R)- and 4(S)-(5-phenylpentyl)-glutamic acids (C5R and C5S analogues) were investigated. In the presence of 5 microM C5R or C5S, excitatory postsynaptic potentials (EPSPs), elicited by stimulating the Schaffer collateral-commissural pathway, recorded in the hippocampal CA1 region on rat brain slices were reduced by more than 50% of the control. Both the NMDA receptor- and the non-MNDA receptor-mediated components of the EPSP were attenuated to the similar extent. The blockade of the presynaptic input, by 0.5 microM tetrodotoxin (TTX), resulted in that C5 analogues no longer inhibited the depolarization induced by AMPA or NMDA on brain slices. On the other hand, the AMPA- and NMDA-induced whole cell inward current of the dissociated hippocampal neurons was not affected by the presence of C5 analogues, investigated with the whole cell patch-clamping technique. These results suggest that the site of the inhibitory action of C5R and C5S may be at the presynaptic termini and that the release of the excitatory neurotransmitter, most likely the glutamate, may be tampered.