Direct chromatographic determination of dissociation rate constants of ligand-receptor complexes: assessment of the interaction of noncompetitive inhibitors with an immobilized nicotinic acetylcholine receptor-based liquid chromatography stationary phase

Anal Chem. 2005 Aug 15;77(16):5421-6. doi: 10.1021/ac0504464.

Abstract

A liquid chromatographic stationary phase containing immobilized membranes from a cell line expressing the alpha3beta4 subtype of the neuronal nicotinic acetylcholine receptor (nAChR) has been used to assess dissociation rate constants (kd) of 12 noncompetitive inhibitor-nAChR complexes. The pharmacological effects of the noncompetitive inhibitors, expressed as percent recovery of activity at 7 min and 4 h postexposure to the inhibitor, were also determined. The results demonstrate that the kd values correlated with the pharmacological effect and that this approach can be used to identify molecular structures associated with differences in kd values. The method can be adapted for use with membrane-bound receptors, ion channels, and transporters and represents a direct and facile technique for the assessment of dissociation rate constants (kd) of ligand-receptor complexes.

MeSH terms

  • Binding, Competitive
  • Chromatography, Liquid / methods*
  • Kinetics
  • Ligands
  • Molecular Structure
  • Nicotine / analysis*
  • Nicotine / metabolism*
  • Nicotinic Antagonists / analysis*
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / metabolism*
  • Protein Binding
  • Receptors, Nicotinic / metabolism*

Substances

  • Ligands
  • Nicotinic Antagonists
  • Receptors, Nicotinic
  • Nicotine