title: The anticonvulsant effects of the enantiomers of losigamone.
abstract: 1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the effects of the S(+)- and R(-)- enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice. 2 S(+)-losigamone (100 and 200 microM) significantly reduced both potassium- and veratridine-elicited release of glutamate and aspartate from cortical slices. R(-)-losigamone had no effect on release at concentrations up to 400 microM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium-free artificial cerebrospinal fluid. S(+)-losigamone significantly reduced these depolarizations at 50-200 microM whilst R(-)-losigamone had a significant effect at 200-800 microM. 4 DBA/2 mice are susceptible to audiogenic seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg-1, i.p.) significantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg-1. There was no protection at 20 mg kg-1 with R(-)-losigamone. 5 These results, from both in vitro and in vivo experiments, confirm that the pharmacological activity profiles of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid-mediated processes are involved in the mode of action of S(+)-losigamone whereas R(-)-losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)-losigamone might therefore be more effective clinically than losigamone or its R(-)-enantiomer.
authors.affiliation: Department of Pharmacology, Therapeutics and Toxicology, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN.
authors.forename: F A
authors.initials: FA
authors.lastname: Jones
authors.forename: J A
authors.initials: JA
authors.lastname: Davies
mesh_terms: D000596:Amino Acids / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011188:Potassium / Q000494:pharmacology; D012640:Seizures / Q000517:prevention & control; D013237:Stereoisomerism; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D005663:Furans; D014701:Veratridine; C065427:losigame; D011188:Potassium