Anticonvulsant properties of α-, γ-, and α,γ-substituted γ-butyrolactones

Derivatives of γ-butyrolactone (GBL) substituted on the α- and/or γ-positions were synthesized and tested for their effects on behavior in mice, on the electroencephalographs and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including α-ethyl-α-methyl GBL (α-EMGBL), α,α-dimethyl GBL, α,γ-diethyl-α,γ-dimethyl GBL, and γ-ethyl-γ-methyl GBL, prevented seizures induced by pentylenetrazol, β-ethyl-β-methyl-γ-butyrolactone (β-EMGBL), picrotoxin, or all three compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither γ-hydroxybutyrate (GHB) nor α-isopropylidene GBL had any anticonvulsant activity. The anticonvulsant α-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of β-EMGBL, α-EMGBL was tested in incubated hippocampal slices and was found to depress basal activity and antagonize excitation induced by β-EMGBL. These results demonstrate that α-alkyl-substituted GBL, and, to a lesser extent, γ-substituted derivatives are anticonvulsant agents and that their effects are strikingly different from those of GHB or β-alkyl-substituted GBLs, which are epileptogenic. Possibly β- and α-substituted GBLs act at the same site as agonists and antagonists, respectively.