J. Knabe et al., 1,5-BENZODIAZEPINES .2. DIAMETRICALLY OPP OSITE CNS-EFFECTS BETWEEN THE ENANTIOMERS OF 2 3,3-DIALKYL-1,5-BENZODIAZEPINE-2,4-DIONES, Archiv der pharmazie, 328(1), 1995, pp. 59-66
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.