Electrophysiological characterization of a novel potent and orally active NMDA receptor antagonist: CGP 37849 and its ethylester CGP 39551.

The selectivity and potency of the novel competitive N-methyl-D-aspartate (NMDA) receptor antagonists, CGP 37849 and CGP 39551, were investigated in vitro and in vivo using electrophysiological approaches. Like the reference blocker DL-AP5, both compounds acted in vitro (hippocampus, substantia nigra, spinal cord) to antagonize the excitatory actions of exogenously administered NMDA as well as the synaptically elicited, physiological NMDA receptor responses in hippocampus and spinal cord. In all isolated preparations CGP 37849 was more potent than CGP 39551, and 5- to 10-fold more potent than DL-AP5. Neither compound showed any marked effect on responses evoked by quisqualate and kainate. NMDA excited dopaminergic cells in the pars compacta region of the substantia nigra in a concentration-dependent manner. This effect also could be selectively antagonized by CGP 37849 and CGP 39551. In the anaesthetized rat, excitatory responses of hippocampal pyramidal cells evoked by iontophoretic application of NMDA were antagonized by CGP 37849 and CGP 39551 following their oral administration without reducing quisqualate or kainate responses. In contrast to the in vitro situation, CGP 39551 was more potent than CGP 37849 in vivo. Effective doses were 30 mg/kg p.o. for CGP 39551 and 100 mg/kg p.o. for CGP 37849. In conclusion, it is demonstrated that CGP 37849 and CGP 39551 selectively antagonize NMDA evoked neuronal responses in vivo and in vitro and that the drugs are centrally active following their oral administration.