SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF A NEW SERIES OF SUBSTITUTED BENZOYL-GAMMA-BUTYROLACTONE DERIVATIVES

A series of substituted benzoyl-gamma-butyrolactones (1-3) has been sy nthesized and tested for their ability to affect central dopaminergic and GABAergic function in comparison to gamma-butyrolactone (GEL). Sim ilarly to GEL, alpha-, beta- and gamma-substituted GBLs 1-3 with one o r more chlorine on the phenyl ring were found to induce central depres sant effects in rats, though at different degrees. However, the test c ompounds modified dopamine (DA) metabolism in rat striatum differently from GEL. In fact, whereas GEL increased both DA and dihydroxyphenyla cetic acid (DOPAC) content, GEL derivatives 1-3 increased DA levels, b ut reduced the DOPAC concentration. Moreover, some of them, unlike GEL , effectively antagonized pentylenetetrazole (PTZ)-induced seizures in mice. In particular, alpha-3,5-dichlorobenzoyl-GBL (1g) was effective at a dose as low as 36 mg/kg in decreasing the number of animals havi ng convulsions. However, in vitro addition and in vivo administration of the test compounds failed to modify [S-35]-t-butylbicyclo-phosphoro thionate ([S-35]-TBPS) binding, which is a very sensitive tool for rev ealing changes in the GABAergic function.