In vitro screening for anticonvulsant-induced teratogenesis: Structure-activity relationships in the barbiturate and branched chain carboxylic acid classes.

The ability of in vitro antiproliferative and cytotoxicity assay systems to discriminate teratogenic potential in closely related anticonvulsant agents is described. A non-teratogenic analogue of valproate-valpramide-had no antiproliferative effect in C6 glioma over the concentration range in which it was an effective anticonvulsant and in which valproate exerts its teratogenic and antiproliferative effects. Barbiturate cytotoxicity in primary cultures of cerebral cortex neurons was only apparent with amobarbital, pentobarbital and thiopental, in which carbon 5 of the parent barbiturate ring is modified with a methyl substituted 4-carbon chain. This effect was independent of branching within the chain and was exacerbated by replacing oxygen with sulphur on carbon 2 of the parent barbiturate ring.