Effects of U-84681 on Voltage-Gated NA+ and K+ Channels in N1E-115 Mouse Neuroblastoma Cells
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U-54494A, 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzamide, has been shown to be a potent and long-acting anticonvulsant in experimental animals, probably due to its ability to block voltage-gated Na+ and K+ channels (Zhu and 1m 1992a; Zhu and Im, 1992b). The persistence of anticonvulsant activity after a decline in its concentration in the brain implies its conversion into active metabolites (VonVoigtlander, et al.,1989). In this study, one of the identified metabolites, U-84681 [(2-ketocyclohexyl}-3,4-dichlorobenzamide], was tested for its effect on voltage-gated ion channels in N1E-115 mouse neuroblastoma cells using the whole cell patch clamp technique. This compound is unique in not possessing a protonatable amine group which is present in U-54494A and its other metabolites. U-84681 blocked voltage-gated Na+ channels in N1E-115 neuroblastoma cells in a voltage- and use- dependent manner by interacting with the channels in the slow inactivating state. The drug also blocked voltage-gated K+ channels. U-54494A, the parent drug, has been shown earlier to have similar actions on both channels. Although the modes of interaction with the ion channels were similar between U- 54494A and U-84681, the metabolite was far less potent in blocking Na+ or K+ channels compared to the parent drug. These observations have led us to conclude that the protonatable amine group of U-54494A and its analogs plays a vital role in the blocking of the voltage-gated Na+ and K+ channels and may be responsible for their anticonvulsant activity.