title: The stereo-isomers of the anticonvulsant ARL 12495AA limit sustained repetitive firing and modify action potential properties of rat hippocampal neurons in vitro.
abstract: 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 microM reaching a near maximum at 400 microM. Comparing the potencies of the two isomers, IC50 values of 55 and 39 microM 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 microM) 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.
authors.affiliation: Department of Physiology, University of Leeds, U.K.
authors.forename: S K
authors.initials: SK
authors.lastname: Norris
authors.forename: A E
authors.initials: AE
authors.lastname: King
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000187:drug effects*; D066298:In Vitro Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000927:Anticonvulsants; D010627:Phenethylamines; C089135:FPL 12495