[1,5-Benzodiazepines. 2. Diametrically opposite central nervous system actions of the two stereoisomers of 3,3-dialkyl-1,5-benzodiazepine-2,4-diones].
I.p. applicated S(+)-1, R(-)-1 und rac. 1 prolonged hexobarbital sleeping in rats. The rac. 8-chloro compound 3 given i.p. produced no prolongation. Determination of rac. 1 in serum and tissues of rats 30 min after 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 determination. I.v. applicated, the enantiomers of 1 and 3 showed diametrically opposite CNS-effects: The S(+)-enantiomers were convulsively active as pentetrazol, whereas the R(-)-enantiomers were CNS depressant active prolonging hexobarbital sleeping time dose-dependently. High doses 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 the benzodiazepine binding site of the GABA-receptor.--Enantioselective differences for the binding of the 1-enantiomers to human serum albumin were found, too. R(-)-1 was bound to a greater extent than S(+)-1.
Knabe
J
J
Fachrichtung Pharmazeutische Chemie, Universität des Saarlandes.
Büch
H P
HP
Bender
S
S
D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000138:chemical synthesis* / Q000494:pharmacology; D003292:Convulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D018755:GABA Agonists / Q000138:chemical synthesis / Q000494:pharmacology; D018756:GABA Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D002492:Central Nervous System Depressants; D003292:Convulsants; D018755:GABA Agonists; D018756:GABA Antagonists; D001569:Benzodiazepines