Conformation selectivity in the binding of diazepam and analogues to α1-acid glycoprotein

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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 α1-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.

Original languageEnglish
Pages (from-to)4857-4862
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number14
DOIs
Publication statusPublished - Jul 15 2007

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Keywords

  • Benzodiazepine conformation
  • Diazepam
  • Genetic variants
  • Induced circular dichroism
  • Protein binding
  • α-Acid glycoprotein

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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