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 greater than 300 mg/kg). In rats,
3-F-PCA also showed a strikingly low oral toxicity (TD50 greater than 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.