Sulpiride, Amisulpride, Thioridazine, and Olanzapine: Interaction with Model Membranes. Thermodynamic and Structural Aspects

ACS Chem Neurosci. 2017 Jul 19;8(7):1543-1553. doi: 10.1021/acschemneuro.7b00057. Epub 2017 Apr 12.

Abstract

Neuroleptic drugs are widely applied in effective treatment of schizophrenia and related disorders. The lipophilic character of neuroleptics means that they tend to accumulate in the lipid membranes, impacting their functioning and processing. In this paper, the effect of four drugs, namely, thioridazine, olanzapine, sulpiride, and amisulpride, on neutral and negatively charged lipid bilayers was examined. The interaction of neuroleptics with lipids and the subsequent changes in the membrane physical properties was assessed using several complementary biophysical approaches (isothermal titration calorimetry, electron paramagnetic resonance spectroscopy, dynamic light scattering, and ζ potential measurements). We have determined the thermodynamic parameters, that is, the enthalpy of interaction and the binding constant, to describe the interactions of the investigated drugs with model membranes. Unlike thioridazine and olanzapine, which bind to both neutral and negatively charged membranes, amisulpride interacts with only the negatively charged one, while sulpiride does not bind to any of them. The mechanism of olanzapine and thioridazine insertion into the bilayer membrane cannot be described merely by a simple molecule partition between two different phases (the aqueous and the lipid phase). We have estimated the number of protons transferred in the course of drug binding to determine which of its forms, ionized or neutral, binds more strongly to the membrane. Finally, electron paramagnetic resonance results indicated that the drugs are localized near the water-membrane interface of the bilayer and presence of a negative charge promotes their burying deeper into the membrane.

Keywords: EPR; Neuroleptics; calorimetry; drug−membrane interactions; liposomes; ζ potential.

MeSH terms

  • Amisulpride
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / pharmacology
  • Benzodiazepines / chemistry*
  • Benzodiazepines / pharmacology
  • Calorimetry
  • Dynamic Light Scattering
  • Electron Spin Resonance Spectroscopy
  • Membranes, Artificial*
  • Models, Chemical
  • Molecular Structure
  • Olanzapine
  • Phosphatidylcholines / chemistry
  • Phosphatidylglycerols / chemistry
  • Protons
  • Sulpiride / analogs & derivatives*
  • Sulpiride / chemistry*
  • Sulpiride / pharmacology
  • Thermodynamics
  • Thioridazine / chemistry*
  • Thioridazine / pharmacology
  • Water / chemistry

Substances

  • Antipsychotic Agents
  • Membranes, Artificial
  • Phosphatidylcholines
  • Phosphatidylglycerols
  • Protons
  • Water
  • Benzodiazepines
  • Sulpiride
  • Amisulpride
  • 1-palmitoyl-2-oleoylglycero-3-phosphoglycerol
  • Thioridazine
  • Olanzapine
  • 1-palmitoyl-2-oleoylphosphatidylcholine