1,5-BENZODIAZEPINES .2. DIAMETRICALLY OPP OSITE CNS-EFFECTS BETWEEN THE ENANTIOMERS OF 2 3,3-DIALKYL-1,5-BENZODIAZEPINE-2,4-DIONES

I.p. applicated S(+)-1, R(-)-1 und rac. 1 prolonged hexobarbital sleep ing in rats. The rac. 8-chloro compound 3 given i.p. produced no prolo ngation. Determination of rac. I in serum and tissues of rats 30 min a fter i.p. administration of 50 mg/kg showed that rac. 1 was detectable in serum and brain, yet its concentration was below the limit of dete rmination. I.v. applicated, the enantiomers of 1 and 3 showed diametri cally opposite CNS-effects: The S(+)-enantiomers were convulsively act ive as pentetrazol, whereas the R(-)-enantiomers were CNS depressant a ctive prolonging hexobarbital sleeping time dose-dependently. High dos es of diazepam antagonized dose-dependently the convulsive action of S (+)-1 supporting the hypothesis that this enantiomer acted as a strong inverse agonist, whereas R(-)-1 produced weak agonistic activity at t he benzodiazepine binding sire of the GABA-receptor. - Enantioselectiv e differences for the binding of the 1-enantiomers to human serum albu min were found, too. R(-)-1 was bound to a greater extent than S(+)-1.