In the present study, we investigated structure-permeability relationships for the blood-brain barrier (BBB) of 16 imipramine and phenothiazine derivatives. The compounds belong to structurally related chemical classes of catamphiphiles, representatives of which have previously been investigated for membrane activity and ability to overcome multidrug resistance (MDR) in tumour cells. These studies show that phenothiazines and structurally related drugs (imipramines, thioxanthenes, acridines) interact with membrane phospholipids, and additionally inhibit the MDR transport P-glycoprotein. This study aimed to identify common 3D structural characteristics of these compounds related to their mechanism of transport across the BBB. For this purpose Genetic Algorithm Similarity Programme (GASP), Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) were applied. The results demonstrate the importance of the spatial distribution of molecular hydrophobicity for the BBB penetration of the investigated compounds. It suggests that the compounds should follow a specific profile of two hydrophobic and one hydrophilic centres in a particular space configuration, for optimal BBB penetration.