Interactions of beta-blockers with model lipid membranes: molecular view of the interaction of acebutolol, oxprenolol, and propranolol with phosphatidylcholine vesicles by time-dependent fluorescence shift and molecular dynamics simulations
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24681296
DOI
10.1016/j.ejpb.2014.03.013
PII: S0939-6411(14)00102-7
Knihovny.cz E-resources
- Keywords
- Drug-membrane interactions, Dtmac, Generalized polarization, Laurdan, Lipid hydration, MD, NME, Prodan, Solvent relaxation,
- MeSH
- Acebutolol metabolism MeSH
- Adrenergic beta-Antagonists metabolism MeSH
- Fluorescence MeSH
- Fluorescent Dyes metabolism MeSH
- Phosphatidylcholines metabolism MeSH
- Glycerol metabolism MeSH
- Lipid Bilayers metabolism MeSH
- Liposomes metabolism MeSH
- Membrane Lipids metabolism MeSH
- Oxprenolol metabolism MeSH
- Propranolol metabolism MeSH
- Molecular Dynamics Simulation MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 1-palmitoyl-2-oleoylphosphatidylcholine MeSH Browser
- Acebutolol MeSH
- Adrenergic beta-Antagonists MeSH
- Fluorescent Dyes MeSH
- Phosphatidylcholines MeSH
- Glycerol MeSH
- Lipid Bilayers MeSH
- Liposomes MeSH
- Membrane Lipids MeSH
- Oxprenolol MeSH
- Propranolol MeSH
Since pharmacokinetic and pharmacodynamic activities of drugs are often related to their interactions with biomembranes, it is of high interest to establish an approach for the characterization of these interactions at the molecular level. For the present study, beta-blockers (oxprenolol, propranolol, and acebutolol) were selected due to their well described nonspecific membrane effects (NME). Their interactions with model lipid membranes composed of palmitoyloleoylphosphatidylcholine (POPC) were studied using Time-Dependent Fluorescence Shift (TDFS) and Generalized Polarization (GP) as well as molecular dynamics (MD) simulations. Liposomal vesicles were labeled with fluorescent membrane polarity probes (Laurdan, Prodan, and Dtmac). Increasing beta-blocker concentrations (0-10 mM for acebutolol and oxprenolol, and 0-1.5 mM for propranolol) significantly rigidifies the lipid bilayer at the glycerol and headgroup level, which was detected in the steady-state and in the time-resolved fluorescence data. The effects of propranolol were considerably stronger than those of the two other beta-blockers. The addition of fluorescent probes precisely located at different levels within the lipid bilayer revealed the insertion of the beta-blockers into the POPC bilayer at the glycerol backbone level, which was further confirmed by MD simulations in the case of propranolol.
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