Inhibition of neuronal Na+ channels by the novel antiepileptic compound DCUKA: identification of the diphenylureido moiety as an inactivation modifier.
In a previous analysis of existing antiseizure compounds, we suggested that a common diphenylureido moiety was responsible for the activity-dependent, Na(+) channel blocking actions of these drugs (L. D. Snell et al., 2000, J. Pharmacol. Exp. Ther. 292: 215-227). Thus the novel diphenylureido compound [N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyquinoline] DCUKA was developed to incorporate the diphenylureido pharmacophore into a structure that also acted as an NMDA receptor antagonist. DCUKA has previously been shown to have antiepileptic properties in animals, and in the present study the actions of DCUKA on Na(+) currents were characterized using transfected cells that stably expressed the rat brain Na(v)1.2 channel isoform. In whole-cell voltage-clamp recordings, DCUKA reduced Na(+) currents in a dose- and membrane potential-dependent fashion, with an apparent 1:1 stoichiometry of drug:channel interaction. Characterization of the effects of DCUKA on Na(+) channel function strongly suggested that DCUKA acts by enhancing Na(+) channel inactivation. Thus in the presence of DCUKA, Na(v)1.2 channels showed reduced availability in steady-state inactivation protocols, displayed use-dependent inhibition, and were slower to recover from inactivation than untreated channels, while DCUKA showed no significant interaction with the open state of the channel. As previously postulated for the anticonvulsants carbamazepine and phenytoin, these results could be well explained by a model in which the drug preferentially interacts with the fast inactivated state of the channel. Finally, DCUKA was generally more efficacious than carbamazepine in modifying sodium channel behavior. Thus the diphenylureido moiety identified by a structural analysis of classic anticonvulsants appears to be important to the inactivation-specific Na(+) channel inhibition by this class of antiseizure agents.
Wang
Ze-Jun
ZJ
Department of Physiology and Biophysics and Program in Neuroscience, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Snell
Lawrence D
LD
Tabakoff
Boris
B
Levinson
Simon R
SR
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D015640:Ion Channel Gating / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism
D000927:Anticonvulsants; C403081:N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyquinoline; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D010671:Phenylurea Compounds; D011804:Quinolines; C568253:Scn2A protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels