We previously demonstrated that dextromethorphan (DM; 3-methoxy-17-methylmorphinan) analogs have neuroprotective effects. Here, we investigated the effects of DM, three of its analogs (DF, 3-methyl-17-methylmorphinan; AM, 3-allyloxy-17-methoxymorphian; and CM, 3-cyclopropyl-17-methoxymorphinan) and one of its metabolites (HM; 3-methoxymorphinan), on Na(+) channel activity. We used the two-microelectrode voltage-clamp technique to test the effects of DM, DF, AM, CM and HM on Na(+) currents (I(Na)) in Xenopus oocytes expressing cRNAs encoding rat brain Nav1.2 alpha and beta1 or beta2 subunits. In oocytes expressing Na(+) channels, DM, DF, AM and CM, but not HM, induced tonic and use-dependent inhibitions of peak I(Na) following low- and high-frequency stimulations. The order of potency for the inhibition of peak I(Na) was AM-CM > DM=DF. The DM, DF, AM and CM-induced tonic inhibitions of peak I(Na) were voltage-dependent, dose-dependent and reversible. The IC(50) values for DM, DF, AM and CM were 116.7+/-14.9, 175.8+/-16.9, 38.6+/-15.5, and 42.5+/-8.5 microM, respectively. DM and its analogs did not affect the steady-state activation and inactivation voltages. AM and CM, but not DM and DF, inhibited the plateau I(Na) more effectively than the peak I(Na) in oocytes expressing inactivation-deficient I1485Q-F1486Q-M1487Q (IFMQ3) mutant channels; the IC(50) values for AM and CM in this system were 8.4+/-1.3 and 8.7+/-1.3 microM, respectively, for the plateau I(Na) and 43.7+/-5.9 and 32.6+/-7.8 microM, respectively, for the peak I(Na). These results collectively indicate that DM and its analogs could be novel Na(+) channel blockers acting on the resting and open states of brain Na(+) channels.