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

Fingerprint

Diazepam
Conformations
Glycoproteins
Acids
Enantiomers
Derivatives
Circular Dichroism
Serum Albumin

Keywords

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

ASJC Scopus subject areas

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

Cite this

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title = "Conformation selectivity in the binding of diazepam and analogues to α1-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 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.",
keywords = "α-Acid glycoprotein, Benzodiazepine conformation, Diazepam, Genetic variants, Induced circular dichroism, Protein binding",
author = "I. Fitos and J. Visy and F. Zsila and G. M{\'a}dy and M. Simonyi",
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T1 - Conformation selectivity in the binding of diazepam and analogues to α1-acid glycoprotein

AU - Fitos, I.

AU - Visy, J.

AU - Zsila, F.

AU - Mády, G.

AU - Simonyi, M.

PY - 2007/7/15

Y1 - 2007/7/15

N2 - 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.

AB - 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.

KW - α-Acid glycoprotein

KW - Benzodiazepine conformation

KW - Diazepam

KW - Genetic variants

KW - Induced circular dichroism

KW - Protein binding

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