Summary
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-l,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/1). (R)-enantiomers, however, undergo a ligand type of interaction (Ks=0.036 to 0.12 mmol/1). Prochiral desmethyldiazepam behaves similarly to the (S)-enantiomers of the above compounds. The ligand binding site does not differentiate between M- and P-conformers.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Rendic S., Sunjic V., Kajfez F., Blazwvic N. (1977): Stereoselectivein vitro aromatic oxygenations of chiral 1,4-benzodiazepin-2-ones. In Ullrich V., Hilldebrandt A., Roots I., Estabrook R. W., editors: Microsomes and drug oxidations, Oxford, Pergamon Press, pp. 622–627.
Kolbah D., Blazevic N., Hannoun M., Kajfez F., Kovac T., Rendic S., Sunjic V. (1977): Stereoselectivein vitro aromatic-ring oxygenations of chiral 1,4-benzodiazepin-2-ones. Helv. Chim. Acta,60: 265–283.
Rendic S., Sunjic V., Kajfez F., Kiasinc L., Mildner P. (1974): Stereoselectivity in enzymic biotransformation of chiral and achiral 1,3-dihydro-2H-1,4-benzodiazepin-2-ones. Chimia (Aarau),28: 232–234.
Vukusic I., Rendic S., Misic M., Oochristofis O. 1978): Biotransformation of chiral 1,4-benzodiazepin-2-onesin vivo. 6th EWDM, Leiden, Abstr. no. 76.
Remmer H., Schenkman J., Estabrook R.W., Sasame H., Gilette J., Narasimhulu S., Cooper D.Y., Rosenthal O. (1966): Drug interaction with hepatic microsomal cytochrome. Mol. Pharmacol.2: 187–190.
Schenkman J. B., Remmer H., Estabrook R.W. (1967): Spectral studies of drug interaction with hepatic microsomal cytochrome. Mol. Pharmacol.3: 113–123.
Ullrich V., Nastainczyk W., Ruf. H.H. (1975): Ligand reactions of cytochrome P-450. Biochem. Soc. Transactions,3: 803–807.
Rendic S., Kajfez F. (1980): Interaction of desmethyl-diazepam with rat liver microsomes. Acta Pharm. Jugosl.30: 141–149.
Sunjic V., Kajfez F., Stromar I., Blazevic N., Kolbah D. (1973): Chiral 1,4-benzodiazepines. V. Synthesis and properties of 1,4-benzodiazepines-2-ones containing u-amino acids as a part of the 1,4-diazepine ring J. Heterocyclic. Chem.10: 591–599.
Stromar M., Sunjic V., Kovac T., Kiasinc L., Kajfez F. (1974): Chiral 1,4-benzodiazepines. VII. Concerning the rate of H/D exchange and optical stability of the chiral centre C(3). Croat. Chem. Acta,46: 265–274.
Frommer U.. Ullrich V., Staudinger Hj. (1970): Hydroxylation of aliphatic compounds by liver microsomes. Z. Physiol. Chem.351: 903–912.
Omura T., Sato R. (1964): The carbon monoxide-binding pigment of liver microsomes. J. Biol. Chem.239: 2370–2378.
Lowry O.H., Rosebrough N.J., Farr A.L., Randall R.J. (1951): Protein measurement with the folin phenol reagent. J. Biol. Chem.193: 265–275.
Purcell W., Bass G.E., Clayton J.M. (1973): In Strategy of drug design, Sidney, John Wiley and Sons, pp. 126–143.
Blazevic N., Kajfez F. (1970): A new ring closure of Heterocycl. Chem.7: 1173–1174
Blazevic N., Kajfez F. (1971): A new ring closure of 1,4-benzodiazepines. II. J. Heterocycl. Chem.8: 845–846
Blazevic N., Sunjic V., Crvelin I., Kolbah D., Kajfez F. (1972): 1,4-Benzodiazepines III. Cyclizations paths of hexaminium salts of 2-chloroacetamido-5-chloro-benzophenone and its N-methyl derivative. J. Heterocycl. Chem.9: 531–537.
Sunjic V., Stromar., Kajfez F., Rendic S., Kolbah D. (1973): Chiral 1,4-benzodiazepines VI. Preparation and purification of 3-(S)-methyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepine-2-one. Acta Pharm. Jugoslav.23: 213–217.
Mansuy D., Duppel W., Ruf H.H., Ullrich V. (1974): Phosphines as ligands to microsomal cytochrome P-450. Hoppe-Seylers Z. Physiol. Chem.355: 1341–1349.
Rendic S., Sunjic V., Toso R., Kajfez F., Ruf H.H. (1979): Interaction of Cimetidine with liver microsomes. Xenobiotica,9: 555–564.
Feller D.R., Lubawy W.C. (1973): Interactions of hexobarbital enantiomers with rat liver microsomes. Pharmacology,9: 129–137
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rendic, S., Kajfez, F. Stereochemical characterization of interactions of chiral 1,4-benzodiazepine-2-ones with liver microsomes. European Journal of Drug Metabolism and Pharmacokinetics 7, 137–146 (1982). https://doi.org/10.1007/BF03188731
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03188731