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A selected group of alkoxy- and halogen-substituted 5-benzylidino- and 5-benzylhydantoins was prepared and screened for anticonvulsant activity as measured by the ability of the compound to prevent maximal electroshock and metrazol-induced threshold clonic seizures in rats. The structure-activity studies revealed 5-[3-(trifluoromethyl)benzyl]hydantoin (14) to be the most potent member of the series.

403U76 (5-chloro-[[2-[(dimethylamino)methyl]phenyl]thio]benzene- methanol hydrochloride) is a potent, competitive, inhibitor of 5-hydroxytryptamine (5-HT) and noradenaline reuptake into rat brain synaptosomes. Inhibition of 5-HT uptake in-vivo by 403U76 was demonstrated by potentiation of the behavioural effects of 5-hydroxytryptophan in rats and mice and blockade of p-induced depletion of 5-HT in rats. The firing of 5-HT-ergic dorsal raphe neurons in rats was decreased after intravenous administration of low doses of 403U76 as would be predicted for a 5-HT uptake inhibitor. 403U76 antagonized tetrabenazine-induced sedation, an effect associated with inhibitors of noradrenaline uptake, but not with inhibitors of 5-HT uptake. Thus 403U76 affects noradrenergic as well as 5-HT-ergic neurotransmission in-vivo. Potential anxiolytic activity was indicated by reductions in isolation-induced vocalizations in neonates after 403U76 treatment. Low intravenous doses of 403U76 were well tolerated and had no sustained cardiovascular effects. There were no deleterious behavioural side-effects at active doses. Effects observed on isolated tissues or transmitter receptors occurred only at very high concentrations and were pharmacologically unimportant. Thus 403U76 can be considered a potential antidepressant/anxiolytic agent that is a potent, selective inhibitor of 5-HT and noradrenaline reuptake.

The synthesis of the enantiomers of bupropion, (rac)-2-tert-butylamino-3'-chloropropiophenone 1 (Wellbutrin) is described. The enantiomers were compared with the racemate in both the tetrabenazine-induced sedation model and the inhibition of uptake of biogenic amine assay. No significant differences were found in their potencies to reverse tetrabenazine-induced sedation in mice or in their IC50 values as inhibitors of biogenic amine uptake into nerve endings obtained from mouse brain.