Research ReportBlockade 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 IC50 of fomocaine was 10.3 μM, and the IC50 for the more hydrophilic Oe 9000 was 4.5 μM. These IC50 values are more than one order of magnitude lower than the corresponding IC50 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.

Research Highlights► Fomocaine and the new Oe 9000 are local anesthetics with a phenoxymethyl group. ► Whole-cell mode (patch-clamp) on rat DRG neurons measured drug-modified Na+ currents. ► Both drugs reversibly reduced slowly activating and inactivating TTX-R Na+ currents. ► Both drugs reversibly reduced rapidly activating and inactivating TTX-S Na+ currents. ► IC50 (fomocaine): 10.3 μM; IC50 (Oe 9000): 4.5 μM for TTX-R Na+ currents.