Bovine brain phosphatidylinositol transfer protein. Selective inhibition by chlorpromazine and other amphiphilic amines.

Cationic amphiphilic amines of varied pharmacological activity were evaluated as modulators of the protein-catalyzed, intermembrane transfers of phosphatidylinositol and phosphatidylcholine. The catalytic agent was brain phosphatidylinositol transfer protein; the membrane system consisted of two populations of single bilayer phospholipid vesicles. The majority of the amines tested caused decreases in phospholipid transfer activity with the relative potencies in the following order: chlorpromazine greater than dibucaine greater than propranolol much greater than tripelennamine approximately chloroquine greater than dipyridamole. Concentrations required for 50% inhibition of phosphatidylinositol transfer were 0.24 mM chlorpromazine, 0.46 mM dibucaine, and 0.78 mM propranolol. The phosphatidylcholine transfer activity of this protein was somewhat less sensitive to these compounds. Comparison of chlorpromazine and its quaternary amine analogue, methochlorpromazine, at different pH values indicated that the observed inhibition can be attributed in large part to the charged forms of the amphiphiles. Direct association of methochlorpromazine with egg phosphatidylcholine bilayers was demonstrated by molecular sieve chromatography; no such association of the amphiphile with phosphatidylinositol transfer protein was apparent. Anionic agents, such as indomethacin, phenylbutazone, and tolmetin, were without significant effect on protein-catalyzed phospholipid transfers. Electrostatic interaction between the cationic amines and anionic or zwitterionic phospholipids, forming ion pairs in the lipid bilayers, is suggested as a possible molecular mechanism for the observed inhibition.