The dissociative anesthetics phencyclidine (PCP) and MK-801 are powerful anticonvulsants in a wide variety of animal seizure models. However, undesirable side effects that occur in the same dosage range as seizure protection limit their practical usefulness in the treatment of seizure disorders. Despite their unfavorable therapeutic indices, PCP and MK-801 can be considered prototypes upon which to base the design of less toxic and potentially more clinically useful antiepileptic drugs. We have previously described several phenylcyclohexylamine (PCA) analogs that are effective anticonvulsants in the mouse maximal electroshock (MES) test and have relatively less motor toxicity than PCP. During the present reporting period, we completed a study showing that the PCA analogs l-phenylcyclopentylamine and 1(3-fluorophenyl)cyclohexylamine have particularly favorable toxicity profiles, especially when administered orally; the results with 3-F-PCA in the rat were especially notable: its anticonvulsant ED50 was 0.8 mg/kg p.o., whereas it failed to cause motor toxicity even at high doses (50 mg/kg). Studies were also conducted on 5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten-5, 10-imine (ADCl), a tricyclic compound which is structurally related to MK-801 and the commonly used antiepileptic carbamazepine. ADCI was a potent anticonvulsant in the MES test (ED50,8.9 mg/kg) and showed a six-fold higher therapeutic index than PCP. Unlike carbamazepine, ADCl was able to protect against PTZ (ED50, 37 mg/kg) and NMDA-induced seizures (ED50,15 mg/kg). The ability of ADCI to block NMDA receptor-mediated responses was confirmed in cellular ' electrophysiological studies (see project Z01 NS 02732-05 MNB). We conclude that ADCI may offer advantages over carbamazepine in the treatment of resistant seizure disorders because of its ability to block NMDA receptor-mediated responses. ADCI was observed to be a particularly effective antagonist of seizures induced in mice by the K+ channel blocking agent 4-aminopyridine (4-AP; ED50, 7.1 mg/kg). To investigate the 4-AP model further, the activities of a wide variety of anticonvulsant drugs were examined for their ability to protect against 4-AP-induced seizures and lethality. It was concluded that drugs with a phenytoin-like spectrum of activity (that are believed to block seizure spread) are effective in this model, suggesting that ADCl may also act by this mechanism.
