title: Conformation selectivity in the binding of diazepam and analogues to alpha1-acid glycoprotein.
abstract: Diazepam, a 1,4-benzodiazepine lacking chiral centre, exists in an equimolar mixture of two chiral conformers. Induced circular dichroism spectra for the binding of diazepam and its 3,3-dimethyl substituted analogues to alpha1-acid glycoprotein (AGP) revealed that opposite to human serum albumin, AGP preferably binds the P-conformers. Accordingly, slightly favoured binding of (R)-enantiomers of 3-alkyl derivatives having P-conformation was found. In case of 3-acyloxy derivatives, however, AGP preferably binds the (S)-enantiomers. Studies with the separated genetic variants of AGP proved similar binding affinities, but markedly different conformation selectivities. For diazepam bound by the F1-S variant, a P/M selectivity of about 2 could be estimated.
authors.affiliation: Department of Molecular Pharmacology, Institute of Biomolecular Chemistry Chemical Research Center, Hungarian Academy of Sciences, PO Box 17, H-1525 Budapest, Hungary. fitosi@chemres.hu
authors.forename: Ilona
authors.initials: I
authors.lastname: Fitos
authors.forename: Júlia
authors.initials: J
authors.lastname: Visy
authors.forename: Ferenc
authors.initials: F
authors.lastname: Zsila
authors.forename: György
authors.initials: G
authors.lastname: Mády
authors.forename: Miklós
authors.initials: M
authors.lastname: Simonyi
mesh_terms: D002942:Circular Dichroism; D003975:Diazepam / Q000031:analogs & derivatives* / Q000737:chemistry*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008968:Molecular Conformation; D009961:Orosomucoid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry
chemical_list: D009961:Orosomucoid; D012709:Serum Albumin; D003975:Diazepam