GAMMA-AMINOBUTYRIC ACID (GABA) RECEPTOR STIMULATION .1. NEURO-PHARMACOLOGICAL PROFILES OF PROGABIDE (SL-76002) AND SL-75102, WITH EMPHASIS ON THEIR ANTICONVULSANT SPECTRA

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 220  (3) , 660-671
Abstract
Progabide (4-{[(4-chloropheny) (5-fluoro-2-hydroxyphenyl)methylene]amino}butanamide) is a GABA receptor agonist which readily enters the brain in mice. In the body, progabide is metabolized to 3 active metabolites, SL 75102 [4-{[(4-chlorophenyl)(5-fluoro-2-hydroxyphenyl)methylene]amino}butyric acid], .gamma.-aminobutyric acid amide [GABA amide] and GABA. Progabide and SL 75102 readily enter the brain and GABA and GABA amide are also formed within this organ. Both progabide and SL 75102 exhibit a broad spectrum of anticonvulsant activities against seizures which involve GABA-mediated events (bicuculline, picrotoxinin and pentylenetetrazol) or which are apparently independent of GABAergic mechanisms (penicillin, strychnine, electroshock and audiogenic seizures). Evidently, direct GABA receptor stimulation is an effective means of controlling convulsions of various origins. Progabide and SL 75102 have relatively minor secondary effects in comparison to commonly used antiepileptics. Myorelaxation occurs, but only at doses higher than the ED50 values in convulsant tests. These compounds are not sedative. These GABA agonists have a complex action in the extrapyramidal system. Anticonvulsant doses are antagonistic to dopamine receptor-mediated behaviors, whereas much lower doses seem to facilitate the effects of dopaminergic transmission.