Comparative assay of anticonvulsant and toxic potencies of sixteen GABAmimetic drugs.

The relative ability of 16 direct and indirect GABAmimetic drugs to elevate the threshold for electroconvulsions and pentetrazole seizures was studied in mice. The following drugs were tested: GABA and its pro drug cetyl GABA, the GABA agonists muscimol, THIP and progabide, the inhibitors of the high affinity GABA uptake (-)- and (+)-nipecotic acid ethyl ester, (+/-)-nipecotic acid methyl ester, (+/-)-cis-4-hydroxynipecotic acid methyl ester and guvacine methyl ester, and the inhibitors of GABA degradation aminooxyacetic acid, gabaculine, gamma-acetylenic GABA, gamma-vinyl GABA and ethanolamine-O-sulphate. Valproic acid was induced as a reference standard. All drugs were administered intraperitoneally and their anticonvulsant potencies were compared at the previously established time of peak drug effect. All GABAmimetics gave rise to significant, dose-dependent threshold elevations. Most potent were muscimol, THIP and Cetyl GABA, and least potent were gamma-vinyl GABA and ethanolamine-O-sulphate. Determination of minimal neurotoxicity by means of the chimney test indicated that the anticonvulsant effect of most GABAmimetics was impaired by a narrow margin of safety. Only cetyl GABA, aminooxyacetic acid and progabide exhibited satisfactory margins of safety similar to those of valproic acid in any particular test. Based on the present data, cetyl GABA and progabide appear to be the most interesting compounds examined besides valproic acid and both GABAmimetics may be interesting as potential antiepileptic drugs.