Three compounds reportedly blocking the N-methyl-D-aspartate (NMDA) receptor, namely 2-amino-5-phosphonovalerate, gamma-D-glutamylglycine and 3-hydroxy-2-quinoxalinecarboxylic acid, were injected subdurally onto the cortex of freely moving rats. All 3 compounds effectively suppressed behavioral and electrographic seizure activity induced by strychnine, morphine and picrotoxin that were administered via the same route. The cortical application of the NMDA-receptor antagonists did not induce behavioral or electrographic changes, and behavioral side-effects commonly observed following intracerebroventricular administration of these compounds were absent. The anatomical separation of anticonvulsant action and side-effects induced by these compounds suggests that this class of compounds may eventually be useful as antiepileptic drugs.