Blockade of TTX-resistant and TTX-sensitive Na+ currents in cultured dorsal root ganglion neurons by fomocaine and the fomocaine derivative Oe 9000.
Fomocaine and its new derivative Oe 9000 are local anesthetics in which the inner aromatic moiety carries a phenoxymethyl substituent and is linked to the tertiary amine by an alkylene chain, rendering these compounds considerably lipophilic and increasing their chemical and metabolic stability. Although fomocaine was used for surface anesthesia, the presumed mode of action of fomocaine and Oe 9000, the blockade of voltage-gated Na(+) currents in neurons, has not been investigated. In the present experiments we used the whole-cell mode of the patch-clamp technique and studied the effect of both drugs on voltage-gated Na(+) currents in isolated and cultured dorsal root ganglion (DRG) neurons from adult rats. Both drugs reversibly reduced slowly activating and inactivating tetrodotoxin-resistant (TTX-R) Na(+) currents as well as rapidly activating and inactivating TTX-sensitive (TTX-S) Na(+) currents at low micromolar concentrations. For the reduction of TTX-R Na(+) currents the IC(50) of fomocaine was 10.3μM, and the IC(50) for the more hydrophilic Oe 9000 was 4.5μM. These IC(50) values are more than one order of magnitude lower than the corresponding IC(50) of other local anesthetics such as lidocaine. Similar as for other local anesthetics, the effects showed a frequency dependence indicating that the compounds preferentially bind to the open and/or inactivated state of the channel. These data establish for the first time the functional suppression of TTX-R and TTX-S Na(+) currents by fomocaine and Oe 9000 in neurons. They support the further research into the use of Oe 9000 as a novel local anesthetic.
Baumgart
Marcus
M
Institut für Biochemie und Biophysik, Biologisch-Pharmazeutische Fakultät, Friedrich-Schiller-Universität Jena, Philosophenweg 12, D-07743 Jena, Germany.
Feller
Christian
C
Natura
Gabriel
G
Dahse
Thomas
T
Schaible
Hans-Georg
HG
Dahse
Ingo
I
D000818:Animals; D001703:Biophysics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D004558:Electric Stimulation; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology*; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000145:classification / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*; D013779:Tetrodotoxin / Q000494:pharmacology
C516051:2,2'-(4-(4-phenoxymethylphenyl)butylimino)diethanol; D004983:Ethanolamines; D010647:Phenyl Ethers; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; C100275:fomocain