Stereochemical characterization of interactions of chiral 1,4-benzodiazepine-2-ones with liver microsomes.

Microsomal P-450 cytochrome are stereoselective toward 7-Chloro-1,3-dihydro-3(S)-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. (S)-1, and 7-chloro-1,3-dihydro-3(S)-isopropyl-5-phenyl-2H-1,4-benzodiazepin-2-one, (S)-2. (S)-enantiomers bind to a substrate binding site which accomodates the stable M-conformation (Ks =0.01 to 0.018 mmol/l). (R)-enantiomers, however, undergo a ligand type of interaction (Ks = 0.036 to 0.12 mmol/l). Prochiral desmethyldiazepam behaves similarly to the (S)-enantiomers of the above compounds. The ligand binding site does not differentiate between M- and P-conformers.