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Several analytical methods are available for determining the partition coefficients of drug compounds in model phospholipid membranes, but such methods provide little information at the molecular level about how the membrane affinity of drugs relates to their interactions with the lipid molecules. A new (2)H nuclear magnetic resonance (NMR) approach has been developed here that quantifies the affinity of (2)H-labeled small molecules for different phospholipid membranes and, simultaneously, provides information on the mechanism of the drug-membrane interaction. In the example given, (2)H NMR analysis of a weakly basic ion pump inhibitor found that the drug partitioned preferentially into membranes of predominantly unsaturated or short-chain phospholipids. The (2)H NMR analysis also suggested that the membrane specificity of the drug was directly correlated to the ability of its phenyl moiety to penetrate into the interior of the lipid bilayer. The (2)H NMR approach could be of value in guiding medicinal chemistry toward or away from structures promoting interactions with specific types of biological membranes.

Original publication

DOI

10.1002/jps.10544

Type

Journal article

Journal

J Pharm Sci

Publication Date

02/2004

Volume

93

Pages

507 - 514

Keywords

Algorithms, Chemical Phenomena, Chemistry, Physical, Enzyme Inhibitors, Lipid Bilayers, Magnetic Resonance Spectroscopy, Membrane Fluidity, Membranes, Artificial, Pharmaceutical Preparations, Phospholipids, Proton Pump Inhibitors, Solubility