title: The neuroleptic drug, fluphenazine, blocks neuronal voltage-gated sodium channels.
abstract: Fluphenazine (Prolixin(R)) is a potent phenothiazine-based dopamine receptor antagonist, first introduced into clinical practice in the late 1950s as a novel antipsychotic. The drug emerged as a 'hit' during a routine ion channel screening assay, the present studies describe our electrophysiological examination of fluphenazine at tetrodotoxin-sensitive (TTX-S) and resistant (TTX-R) voltage-gated sodium channel variants expressed in three different cell populations. Constitutively expressed TTX-S conductances were studied in ND7/23 cells (a dorsal root ganglion-derived clonal cell line) and rat primary cerebrocortical neurons. Recombinant rat Na(V)1.8 currents were studied using ND7/23 cells as a host line for heterologous expression. Sodium currents were examined using standard whole-cell voltage-clamp electrophysiology. Current-voltage relationships for either ND7/23 cell or Na(V)1.8 currents revealed a prominent fluphenazine block of sodium channel activity. Steady-state inactivation curves were shifted by approximately 10 mV in the hyperpolarizing direction by fluphenazine (3 microM for ND7/23 currents and 10 microM for Na(V)1.8), suggesting that the drug stabilizes the inactivated channel state. Fluphenazine's apparent potency for blocking either ND7/23 or Na(V)1.8 sodium channels was increased by membrane depolarization, corresponding IC(50) values for the ND7/23 cell conductances were 18 microM and 960 nM at holding potentials of -120 mV and -50 mV, respectively. Frequency-dependent channel block was evident for each of the cell/channel variants, again suggesting a preferential binding to inactivated channel state(s). These experiments show fluphenazine to be capable of blocking neuronal sodium channels. Several unusual pharmacokinetic features of this drug suggest that sodium channel block may contribute to the overall clinical profile of this classical neuroleptic agent.
authors.affiliation: Department of CNS Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of CNS Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Dong
authors.affiliation: Department of CNS Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: tony.priestley@spcorp.com.
authors.forename: Tony
authors.initials: T
authors.lastname: Priestley
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005476:Fluphenazine / Q000737:chemistry / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006822:Hybrid Cells; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D015394:Molecular Structure; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D005476:Fluphenazine