The dipalmitoyl phosphatidylcholine/water system was employed to study the interaction of phenothiazines with model membranes. In particular the effects of the drugs upon the lipid phase transition were examined using differential scanning calorimetry and NMR spectroscopy. The studied phenothiazines have peripheral (diethazine) or central (chlorpromazine) properties. 2. Both drugs were observed to lower the phase transition temperature of dipalmitoyl phosphatidylcholine. The molar activity of chlorpromazine is somewhat higher than of diethazine. At low concentrations the drugs affect the dipalmitoyl phosphatidylcholine pretransition endotherm. 3. In the 13C NMR spectra of the drug-containing samples the signal of the trimethylammonium group of dipalmitoyl phosphatidylcholine is broadened, whereas a narrowing of the signal of the fatty-acid chain methylene groups is observed. Further, addition of the phenothiazines causes higher values of the effective chemical shift anisotropy of the 31P in the phosphate group, in comparison to the pure dipalmitoyl phosphatidylcholine sample. 4. The results obtained by three different techniques indicate a higher fluidity in the fatty-acid chain region and a mobility reduction of the polar headgroup of the dipalmitoyl phosphatidylcholine molecules in the presence of the phenothiazines. These phenomena can be well accounted for by a model for the incorporation of the phenothiazines in the dipalmitoyl phosphatidyl-choline bilayer, in which the dialkylaminoalkyl chains are located near the polar headgroups and the ring system does not penetrate far beyond the glycerol backbone into the hydrocarbon phase.
