Comparison of the effects of clozapine, chlorpromazine and haloperidol on membrane lateral heterogeneity

The interactions of three neuroleptic drugs, clozapine (CLZ), chlorpromazin e (CPZ), and haloperidol (HPD) with phospholipids were compared using DSC a nd Langmuir balance. Main emphasis was on the drug-induced effects on the l ateral organization of lipid mixtures of the saturated zwitterionic 1,2-dip almitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and the unsaturated acidic phosphatidylserine, brainPS. In multilamellar vesicles (MLV) phase separat ion was observed by DSC at X-PS greater than or equal to 0.05. All three dr ugs bound to these MLVs, abolishing the pretransition at X-drug greater tha n or equal to 0.03. The main transition temperature (T-m) decreased almost linearly with increasing contents of the drugs, CLZ having the smallest eff ect. In distinction from the other two drugs, CLZ abolished the phase separ ation evident in the endotherms for DPPC/brainPS (X-PS = 0.05) MLVs. Compre ssion isotherms of DPPC/brainPS/drug (X-PS = X-drug = 0.05) monolayers reve aled the neuroleptics to increase the average area/molecule, CLZ being the most effective. Penetration into brainPS monolayers showed strong interacti ons between the three drugs and this acidic phospholipid (in decreasing ord er CPZ > HPD > CLZ). Hydrophobic interactions demonstrated using neutral eg gPC monolayers decreased in a different order, CLZ > CPZ > HPD. Fluorescenc e microscopy revealed domain morphology of DPPC/brainPS monolayers to be mo dulated by these drugs, increasing the gel-fluid domain boundary length in the phase coexistence region. To conclude, our data support the view that m embrane-partitioning drugs could exert part of their effects by changing th e lateral organization and thus also the functions of biomembranes. (C) 200 1 Elsevier Science Ireland Ltd. All rights reserved.