The stereo-isomers of the anticonvulsant ARL 12495AA limit sustained repetitive firing and modify action potential properties of rat hippocampal neurons in vitro

The effects of the resolved enantiomers of the anticonvulsant ARL 12495AA ((S,R)-1-methyl-1,2-diphenylethylamine-monohydrochloride), (S)-ARL 12495 and (R)-ARL 12495, on (1) sustained repetitive firing and (2) action potential properties of rat hippocampal neurons were assessed, Whole-cell current-clamp recordings were made from CA1 neurons in slices of adult rat brain. Sustained repetitive firing was evoked by injection of long duration (500 msec) depolarizing (20-400 pA) current pulses. Sustained repetitive firing was inhibited by (S)-ARL 12495 and by (R)-ARL 12495; the threshold concentration was 5 mu M reaching a near maximum at 400 mu M. Comparing the potencies of the two isomers, IC50 values of 55 and 39 mu M were calculated for (S)-ARL 12495 and (R)-ARL 12495, respectively. The actions of the two drugs on neuronal firing were not therefore markedly stereoselective. Examination of individual spike properties revealed a concentration-related (12-400 mu M) and time-dependent increase in the spike duration by (S)-ARL 12495 and (R)-ARL 12495. The spike amplitude and rate-of-rise were attenuated significantly by these two drugs. Both isomers decreased the after-hyperpolarization after a single spike and after trains of spikes. No clear stereoselectivity was demonstrable for the effects of the two enantiomers on action potential properties. Possible mechanisms of action for (S)-ARL 12495 and (R)-ARL 12495 including partial blockade of voltage-sensitive sodium channels and modulation of potassium channels are considered. The possibility that multiple mechanisms of action contribute to the therapeutic efficacy of the anticonvulsant ARL 12495AA is discussed.