Synthesis, pharmacological and biophysical characterization, and membrane-interaction QSAR analysis of cationic amphiphilic model compounds

Cationic amphiphilic drugs have a propensity to interact with biological in terphases. This study was designed to gain more insight into the molecular properties of catamphiphilic drugs which govern this type of interaction. A series of phenylpropylamine model compounds were synthesized in which modi fications were incorporated at the aromatic part of the molecule. The repla cement of Ca-45(2+) from phosphatidylserine monolayers served to monitor dr ug binding to the phospholipid. The influence on the phase-transition tempe rature of liposomes of dipalmitoylphosphatidic acid was measured to assess the perturbing action of the drugs on the structural organization of phosph olipid assemblies. The antiarrhythmic activity of the compounds was determi ned in Langendorff preparations of guinea pig hearts to assess the membrane -stabilizing action. Quantitative structure-activity relationship (QSAR) mo dels for these endpoints were developed using both intra- and intermolecula r QSAR descriptors. Intermolecular membrane-interaction descriptors were de rived from molecular dynamics simulations of the compounds in a model phosp holipid monolayer. QSAR models were derived for all endpoints using partial least-squares regression (PLS) and a genetic algorithm tool, the genetic f unction approximation (GFA). Membrane-interaction descriptors appear to be of a particular importance in explaining the influence of the compounds on the phase-transition temperature of DPPA liposomes, while the other endpoin ts can be adequately modeled by intramolecular descriptors. The calcium-dis placing activity at phosphatidylserine monolayers is governed by the electr ostatic properties of the compounds. Measures of lipophilicity and molecula r size are of particular importance for antiarrhythmic activity. Possible i mprovements to both the molecular modeling and the applied computational pr otocol of membrane-solute systems are identified and discussed.