Partition coefficients, Kp, of four dopamine antagonists (pimozide, fluspirilene, haloperidol and domperidone) between the aqueous phase and lipid bilayer vesicles were determined as a function of lipid chain length, unsaturation and temperature encompassing the range of the lipid phase transition. Model membranes of egg phosphatidylcholine (PC), dimyristoyl (DMPC)-, dipalmitoyl (DPPC)-, distearoyl (DSPC)- and dioleoyl (DOPC)-phosphatidylcholines were studied. Kp values of the drugs are different in the various membranes under study and depend on temperature, aliphatic carbon chain-length and on the presence of unsaturation in the aliphatic lipid chain. First-order transition of membrane lipids from the gel to the liquid crystalline state is accompanied by a sharp increase of the partition coefficient of pimozide and fluspirilene in DMPC, DPPC and DSPC bilayers. For domperidone, Kp values are maximal within the mid-point of phase transition of DMPC and DPPC, while for DSPC Kp values increase progressively with increasing temperature. Haloperidol Kp values display a maximum at the mid-point of phase transition of DMPC, while a progressive increase of Kp is observed in DPPC and DSPC. The four drugs are easily accommodated in bilayers of short aliphatic chain lipids (DMPC), the partition coefficients being 17,137 for pimozide, 18,700 for fluspirilene, 686 for domperidone and 722 for haloperidol, at temperatures 10 degrees C below the mid-point of the lipid phase transition. Except for haloperidol, the partition of the drugs in DOPC (18:1) is higher than that in DSPC (18:0) bilayers at a temperature above the phase transition temperature of both lipids.(ABSTRACT TRUNCATED AT 250 WORDS)