The dissociative anesthetic phencyclidine (PCP) is a powerful anticonvulsant in a wide variety of animal seizure models. However, undesirable side effects which occur in the same dosage range as seizure protection limit its practical usefulness in the treatment of seizure disorders. Despite its unfavorable therapeutic index, PCP can be considered a prototype anticonvulsant upon which to base the design of less toxic and potentially more clinically useful drugs. In this project, we have structurally modified the basic PCP nucleus 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 chemical convulsants pentylenetetrazol (PTZ) and N-methyl- D-asparate (NMDA). Motor toxicity was determined with the rotorod ataxia test. PCP and several well-known PCP related compounds such as (+)-(1-phencycyclohexyl)-3-menthyl-piperidine((+)-PCMP) and dexoxadrol had equal potency as anticonvulsants in the MES test and in inducing motor toxicity so that their """"""""therapeutic index"""""""" (TI; ratio of dose causing toxicity in 50% of animals to dose causing seizure protection in 50% of animals) was about 1. These drugs are unlikely to be of practical value in the treatment of seizures. we also observed that PCP and the related compounds noted above were highly potent in preventing NMDA induced seizures, but were weak or ineffective against PTZ induced convulsions. Of the many novel PCP derivatives we screened, several showed enhanced protection against MES seizures relative to their motor toxicity. These compounds differed qualitatively from PCP, (+)-PCMP and dexoxadrol in that they were weaker than expected in blocking NMDA induced seizures than PCP, and they had no activity against PTZ seizures. The most promising structures included cyclohexane ring methylated PCP analogs such as trans-(R)-3-methyl- phenylcyclohexylamine, homologous cycloakylamines such as 1- phenylcyclopentylamine, 1-phenylcycloheptylamine and the conformationally restricted PCP analog 1, 1-pentamethylene- tetrahydroisoquinoline. These drugs had TI's of 3.2-3.7. This can be compared to values of 1.6,3.2,6.9 and 8.1 for the commonly used anticonvulsants valproic acid, phenobarbital, phenytoin and carbamazepine. By including several of the favorable modifications into a single molecule, it may be possible to obtain even further enhancement of the TI.
