Synthesis and pharmacological evaluation of a new series of substituted benzoyl-γ-butyrolactone derivatives

A series of substituted benzoyl-γ-butyrolactones (1-3) has been synthesized and tested for their ability to affect central dopaminergic and GABAergic function in comparison to γ-butyrolactone (GBL). Similarly to GBL, α-, β- and γ-substituted GBLs 1-3 with one or more chlorine on the phenyl ring were found to induce central depressant effects in rats, though at different degrees. However, the test compounds modified dopamine (DA) metabolism in rat striatum differently from GBL. In fact, whereas GBL increased both DA and dihydroxyphenylacetic acid (DOPAC) content, GBL derivatives 1-3 increased DA levels, but reduced the DOPAC concentration. Moreover, some of them, unlike GBL, effectively antagonized pentylenetetrazole (PTZ)-induced seizures in mice. In particular, α-3,5-dichlorobenzoyl-GBL (1g) was effective at a dose as low as 36 mg/kg in decreasing the number of animals having convulsions. However, in vitro addition and in vivo administration of the test compounds failed to modify [35S]-t-butylbicyclophosphorothionate ([35S]-TBPS) binding, which is a very sensitive tool for revealing changes in the GABAergic function.