Lipophilicity and membrane interactions of cationic-amphiphilic compounds:syntheses and structure-property relationships

This study was performed to elucidate the relationship between steric facto rs, lipophilicity, and the potency of cationic-amphiphilic compounds to dis place 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 sys tematic structural variations was synthesized. Lipophilicity values were de termined by chromatographic (RP-HPLC, log D-7.4), shake-flask (log P), and theoretical (CLOGP) techniques. The potency of the compounds to displace ca lcium ions from phosphatidylserine monolayers was determined using a radiot racer technique, employing the isotope Ca-45(2+). The experimental lipophil icity values of several isomeric biphenyl- and diphenyl-congeners differ mo re than could be expected from the CLOGP-calculations and show a good corre lation to the calculated molecular surface areas. Although the affinity of the substances to the phospholipid monolayer tends to increase with lipophi licity, no general interrelation between the two properties could be found. Surprisingly, the assay system (a phospholipid monolayer) was quite sensit ive towards small steric changes at the 'ligand' molecules. Stereochemical factors have a considerable influence on the interaction of solutes with ph ospholipid membranes. It must be questioned whether lipophilicity measures alone, without taking other molecular features into account, can meaningful ly be used to explain or predict the influence of solutes on membrane-relat ed processes and properties. (C) 2001 Elsevier Science BY All rights reserv ed.