The dissociative anesthetics 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 examined the anticonvulsant activity of more than 40 PCP analogs in an attempt to obtain compounds with enhanced anticonvulsant activity relative to their neurotoxic side effects. Drugs were screened for anticonvulsant activity in mice with the maximal electroshock (MES) test and by administration of the chemoconvulsants pentylenetetrazol (PTZ) and N-methyl-D-asparate (NMDA). PCP had approximately equal potency in the MES test and in a motor toxicity test so that its """"""""therapeutic index"""""""" (TI; ratio of dose causing toxicity in 50% of animals to dose causing seizure protection in 50% of animals) was about 1. Certain of the analogs had TI values higher than that of PCP. The most favorable of these were derivatives of 1-phenylcyclohexylamine modified by (1) certain stereochemically orientated cyclohexane ring methyl substituents, (2) ortho substituents on the phenyl ring, and (3) contraction of the cyclohexane ring. Studies were also conducted on compounds related to the dibenzocyclohepteneimine MK-801. Of particular interest is 5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCl) which is structurally related to the commonly used antiepileptic carbamazepine. ADCl was a potent anticonvulsant in the MES test (ED50, 8.9 mg/kg) and showed a six-fold higher TI 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 ADCl to block NMDA receptor-mediated responses was confirmed in cellular electrophysiological studies (see project Z01 NS 02732-04 MNB). We conclude that ADCl may offer advantages over carbamazepine in the treatment of resistant seizure disorders because of its ability to block NMDA receptor-mediated responses.
