Synthesis and structure-activity relationships (SAR) are described for a series of N,N'-diarylguanidines related to N-acenaphth-5-yl-N'-(4-methoxynaphth-1-yl)guanidine (3) as anticonvulsants through blockade of sodium channels. SAR studies on compound 3 led to several simpler diphenylguanidines with improved in vitro and in vivo activity. Compounds were screened for blockade of sodium channels in a veratridine-induced [14C]guanidinium influx assay (type IIA sodium channels) and for anticonvulsant activity in the audiogenic DBA/2 mouse model. Results indicated that N, N'-diphenylguanidines substituted with flexible and moderate 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 activity. A possible relationship between in vitro and in vivo activity of this compound series and their measured/calculated lipophilicities was investigated. Compounds of this series showed only weak NMDA ion channel-blocking activity indicating that the anticonvulsant activity of these compounds is unlikely to be mediated by NMDA ion channels but, more likely, by acting at voltage-gated sodium channels.