1-Phenylcyclohexylamine (PCA) and its analogues 1-phenylcyclopentylamine (PPA) and 1-(3-fluorophenyl)cyclohexylamine (3-F-PCA) are potent anticonvulsants in the mouse maximal electroshock (MES) seizure test. Unlike the structurally related dissociative anesthetic phencyclidine (PCP), however, which produces motor toxicity at anticonvulsant doses, PCA, PPA, and 3-F-PCA protect against MES seizures at 2.2- to 3.5-fold lower doses than those that cause motor toxicity when administered intraperitoneally (i.p.). In the present study, we evaluated the oral anticonvulsant activity of PCA, PPA, and 3-F-PCA in mice; we also examined 3-F-PCA in rats. All the compounds were orally active in the mouse MES seizure test (ED50 values 14.5, 53.4, and 26.7 mg/kg, respectively). Moreover, 3-F-PCA was especially potent in rats, either when administered i.p. (ED50 0.4 mg/kg vs. 9.4 mg/kg in mice) or orally (ED50 0.8 mg/kg). Surprisingly, however, oral PPA failed to cause motor toxicity in mice even at doses that were many times higher than those that were protective in the MES test (TD50 > 300 mg/kg). In rats, 3-F-PCA also showed a strikingly low oral toxicity (TD50 > 50 mg/kg) in relation to its potency as an anticonvulsant. Like PCP, PCA analogues block N-methyl-D-aspartate (NMDA)-induced behavioral effects and lethality in mice. Moreover, in vitro studies indicate that the compounds act as uncompetitive antagonists of the NMDA receptor-channel complex. Therefore, their anticonvulsant activity may, at least in part, relate to an interaction with NMDA receptors.