Structure-activity relationships of alkyl-substituted γ-butyrolactones and succinimides

Derivatives of β-butyrolactone (GBL) substituted on both the α- and the β-position were synthesized and tested for their effects on behavior in mice, on the electroencephalograph (EEG) and blood pressure of paralyzed-ventilated guinea pigs, and on the electrical activity of incubated hippocampal slices. Several compounds, including α,α,β,β-tetramethyl GBL (TMGBL), α-hydroxy-β,β-dimethyl GBL, endo-bicyclo[2.2.1]hept- and endo-bicyclo[2.2.2]oct-5-ene-2-hydroxymethyl-3-carboxylic acid lactone, produced convulsive seizures in mice and epileptiform EEG discharges in guinea pigs identical with those produced by β-ethyl-β-methyl GBL. Neuronal activity in hippocampal slices was also markedly activated by TMGBL. Seizures and epileptiform discharges produced by these α,β-substituted GBLs were prevented by α-ethyl-α-methyl GBL and ethosuximide but not by phenytoin. A succinimide with the same alkyl substitutions as TMGBL, α,α,α',α'-tetramethylsuccinimide (TMSM), had convulsant properties and a response to anticonvulsant drugs identical with those of TMGBL. A model for the hypothetical site of action of alkyl-substituted GBLs and succinimides explaining the structure-activity relationships is presented. We propose that the absolute requirements for activity of the compounds are (a) a carbonyl oxygen atom on a heterocyclic ring adjacent to an oxygen or a nitrogen atom with an ionizable hydrogen atom and (b) suitable alkyl substituents occupying at least one of the positions α, β, or γ to the carbonyl. Alkyl substitution at the α- and/or γ-position, but not at the β-position, results in a compound which is anticonvulsant. Alkyl substituted at the β-position produces compounds which are convulsant. Thus, it is the presence or absence of alkyl substituents at the β-position that dictates whether a GBL or succinimide will be convulsant or anticonvulsant. Possibly alkyl-substituted GBLs and succinimides act at γ-aminobutyric acid-regulated chloride channels, as does picrotoxin, which has a β-alkyl-substituted GBL moiety that is essential for its activity.