Lipophilicity and membrane interactions of cationic-amphiphilic compounds: syntheses and structure-property relationships.
This study was performed to elucidate the relationship between steric factors, lipophilicity, and the potency of cationic-amphiphilic compounds to displace calcium ions from phosphatidylserine monolayers. The latter property is considered to be a substance/phospholipid affinity measure. A series of cationic-amphiphilic 3-phenyl-N,N-dimethylpropylamine derivatives with systematic structural variations was synthesized. Lipophilicity values were determined by chromatographic (RP-HPLC, log D(7.4)), shake-flask (log P), and theoretical (CLOGP) techniques. The potency of the compounds to displace calcium ions from phosphatidylserine monolayers was determined using a radiotracer technique, employing the isotope (45)Ca(2+). The experimental lipophilicity values of several isomeric biphenyl- and diphenyl-congeners differ more than could be expected from the CLOGP-calculations and show a good correlation to the calculated molecular surface areas. Although the affinity of the substances to the phospholipid monolayer tends to increase with lipophilicity, no general interrelation between the two properties could be found. Surprisingly, the assay system (a phospholipid monolayer) was quite sensitive towards small steric changes at the 'ligand' molecules. Stereochemical factors have a considerable influence on the interaction of solutes with phospholipid membranes. It must be questioned whether lipophilicity measures alone, without taking other molecular features into account, can meaningfully be used to explain or predict the influence of solutes on membrane-related processes and properties.
Klein
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CD
Pharmaceutical Chemistry, ETH Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland. cklein@pharma.ethz.ch
Tabeteh
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GF
Laguna
A V
AV
Holzgrabe
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U
Mohr
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K
D001665:Binding Sites / Q000502:physiology; D002118:Calcium / Q000493:pharmacokinetics; D002412:Cations / Q000737:chemistry* / Q000493:pharmacokinetics; D008051:Lipid Bilayers / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry* / Q000493:pharmacokinetics
D002412:Cations; D008051:Lipid Bilayers; D008563:Membrane Lipids; D010718:Phosphatidylserines; D013501:Surface-Active Agents; D002118:Calcium