3-(2-Carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a novel antagonist at the N-methyl-D-aspartate (NMDA)-preferring subtype of excitatory amino acid receptor, was evaluated in four rodent models of epilepsy, i.e. maximal electroshock seizurees and pentylenetetrazol (PTZ)-induced seizures in mice, epileptic gerbils and amygdala-kindled rats. The effect of CPP after systemic (i.p.) injection was compared with that of the clinical antiepileptics, phenobarbital and diazepam, and in gerbils, in addition, with the effect of the NMDA antagonist 2-amino-5-phosphonopentanoate (AP5) and 2-amino-7-phosphonoheptanoate (AP7). CPP, 5 mg/kg i.p., increasedd the threshold for tonic electroshock seizures bu this effect was associated with motor impairment in the chimney test whereas phenobarbital had comparable anticonvulsant potency without motor impairment. The threshold for clonic PTZ seizures was increased by CPP only at high doses (20 mg/kg) which induced ataxia and marked motor impairment in the chimney test, whereas both diazepam and phenobarbital were active in this test at doses which exerted no side-effects. CPP, 2–20 mg/kg i.p., could not reduce the severity or duration of focal and generalized clonic seizures or the duration of amygdalar after discharges in the amygdala-kindling model in rats but instead caused ataxia and reduced muscle tone at the higher doses examined. Diazepam and phenobarbital both had anticonvulsant efficacy in this model. CPP at doses of 5–10 mg/kg did not reduce seizure severity in gerbils in which generalized tonic-clonic seizures were induced by air-blast stimulation, but, as in mice and rats, it caused motor mpairmeent. AP7, 100–200 mg/kg, and AP5, 200 mg/kg, significantly reduced seizure severity in gerbils but this effect was associated with marked ataxia and impaired rigthing reflexes. In contrast, diazepam and phenobarbital protected gerbils against generalized tonic-clonic seizures without side-effects. The data indicate that, at least when tested at single doses in traditional rodent models of epilepsy, NMDA antagonists such as CPP do not exert a selective anticonvulsant action.