ANTICONVULSANT PROPERTIES OF ALPHA-SUBSTITUTED, GAMMA-SUBSTITUTED, AND ALPHA,GAMMA-SUBSTITUTED GAMMA-BUTYROLACTONES

Abstract

Derivatives of .gamma.-butyrolactone (GBL) substituted on the .alpha.- and/or .gamma.-positions were synthesized and tested for their effects on behavior in mice, on the EEG and blood pressure of paralyzed-ventilated guinea pigs, and on electrical activity of incubated hippocampal slices. Several compounds, including .alpha.-ethyl-.alpha.-methyl GBL (.alpha.-EMGBL), .alpha.,.alpha.-dimethyl GBL, .alpha.,.gamma.-diethyl-.alpha.,.gamma.-dimethyl GBL and .gamma.-ethyl-.gamma.-methyl GBL, prevented seizures induced by pentylenetetrazol, .beta.-ethyl-.beta.-methyl-.gamma.-butyrolactone (.beta.-EMGBL), picrotoxin or all 3 compounds in mice and guinea pigs but had no effect on seizures induced by maximal electroshock or bicuculline. Neither .gamma.-hyroxybutyrate (GHB) nor .alpha.-isopropylidene GBL had any anticonvulsant activity. The anticonvulsant .alpha.-substituted compounds had a potent hypotensive effect and antagonized the hypertensive effect of .beta.-EMGBL. .alpha.-EMGBL was tested in incubated hippocampal slices and depressed basal activity and antagonized excitation induced by .beta.-EMGBL. .alpha.-Alkyl-substituted GBL and, to a lesser extent, .gamma.-substituted derivatives are evidently anticonvuslant agents and their effects are strikingly different from those of GHB or .beta.-alkyl-substituted GBL, which are epileptogenic. Possibly .beta.- and .alpha.-substituted GBL act at the same site as agonists and antagonists, respectively.