Cationic amphiphilic drugs have a propensity to interact with biological interphases. 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 modifications were incorporated at the aromatic part of the molecule. The replacement of (45)Ca(2+) from phosphatidylserine monolayers served to monitor drug binding to the phospholipid. The influence on the phase-transition temperature of liposomes of dipalmitoylphosphatidic acid was measured to assess the perturbing action of the drugs on the structural organization of phospholipid assemblies. The antiarrhythmic activity of the compounds was determined in Langendorff preparations of guinea pig hearts to assess the membrane-stabilizing action. Quantitative structure-activity relationship (QSAR) models for these endpoints were developed using both intra- and intermolecular QSAR descriptors. Intermolecular membrane-interaction descriptors were derived from molecular dynamics simulations of the compounds in a model phospholipid monolayer. QSAR models were derived for all endpoints using partial least-squares regression (PLS) and a genetic algorithm tool, the genetic function 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 endpoints can be adequately modeled by intramolecular descriptors. The calcium-displacing activity at phosphatidylserine monolayers is governed by the electrostatic properties of the compounds. Measures of lipophilicity and molecular size are of particular importance for antiarrhythmic activity. Possible improvements to both the molecular modeling and the applied computational protocol of membrane-solute systems are identified and discussed.