The dynamics and orientation of a lipophilic drug within model membranes determined by 13C solid-state NMR

Methods for determining how a drug interacts with cellular membranes at the molecular level can give valuable insight into the mode of action of the drug and its absorption, distribution and metabolism profile. A procedure is described here to determine the orientation and location of the lipophilic...

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Bibliographic Details
Published in:Physical chemistry chemical physics : PCCP 2008-01, Vol.10 (1), p.178-185
Main Authors: BOLAND, Martin P, MIDDLETON, David A
Format: Article
Language:English
Subjects:
Carbon Isotopes
Chemistry
Colloidal state and disperse state
Computer Simulation
Dimyristoylphosphatidylcholine - chemistry
Exact sciences and technology
General and physical chemistry
Lipid Bilayers - chemistry
Magnetic Resonance Spectroscopy - methods
Magnetic Resonance Spectroscopy - standards
Magnetics
Manganese - chemistry
Membranes
Models, Chemical
Molecular Structure
Reference Standards
Rotation
Trifluoperazine - chemistry
Water - chemistry
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Summary:Methods for determining how a drug interacts with cellular membranes at the molecular level can give valuable insight into the mode of action of the drug and its absorption, distribution and metabolism profile. A procedure is described here to determine the orientation and location of the lipophilic drug trifluoperazine (TFP) intercalated into dimyristoylphosphatidylcholine (DMPC) bilayers, by using a novel combination of high-resolution solid-state nuclear magnetic resonance (SSNMR) methods to observe signals from (13)C within the drug at natural abundance. SSNMR measurements of (1)H-(13)C dipolar couplings for TFP and selective broadening of (13)C NMR peaks by paramagnetic Mn(2+) together suggest a model for the location, orientation and dynamics of the drug within lipid bilayers that offers an explanation for the lysoprotective effect of the drug at low concentrations. The experiments described are straightforward to implement and can be used for the routine analysis of drug-membrane interactions to provide useful information for drug design and structure refinement.
ISSN:1463-9076
1463-9084
DOI:10.1039/b712892d