SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF N,N'-DIARYLGUANIDINES AS POTENT SODIUM-CHANNEL BLOCKERS AND ANTICONVULSANT AGENTS

Synthesis and structure-activity relationships (SAR) are described for a series of N,N'-diarylguanidines related to -acenaphth-5-yl-N'-(4-me thoxynaphth-1-yl)guanidine (3) as anticonvulsants through blockade of sodium channels. SAR studies on compound 3 led to several simpler diph enylguanidines with improved in vitro and in vivo activity. Compounds were screened for blockade of sodium channels in a veratridine-induced [C-14]guanidinium influx assay (type IIA sodium channels) and for ant iconvulsant activity in the audiogenic DBA/2 mouse model. Results indi cated that N,N'-diphenylguanidines substituted with flexible and moder ate size lipophilic groups were preferred over aryl and/or hydrophilic groups for biological activity. Among the compounds studied, n-butyl- and/or n-butoxy-containing guanidines showed superior biological acti vity. A possible relationship between in vitro and in vivo activity of this compound series and their measured/calculated Lipophilicities wa s investigated. Compounds of this series showed only weak NMDA ion cha nnel-blocking activity indicating that the anticonvulsant activity of these compounds is unlikely to be mediated by NMDA ion channels but, m ore likely, by acting at voltage-gated sodium channels.