The impact of charge on chlorpromazine interaction with lipid membranes

Psychiatric disorders, such as schizophrenia, are treated with antipsychotics. One such molecule is chlorpromazine (CPZ) that mainly exerts its therapeutic effect via its antagonist activity on the dopamine D2 receptor. Due to its high lipophilicity, it can partition and accumulate in membranes, which can lead to a delayed full clinical effect, reached weeks after the beginning of treatment. CPZ's insertion in membranes impacts the bilayer's physicochemical properties, which can indirectly impact membrane-embedded receptors, such as the D2 receptor. To further delve into the potential role of phosphatidylserine (PS) in CPZ-membrane interaction and subsequent remodeling of membrane properties, we have investigated CPZ interactions with phosphatidylcholine bilayers, a common model zwitterionic lipid, in the absence and presence of 10% PS. The study provides a comprehensive overview of CPZ's preferential interaction with PS-containing membranes. Altogether, data from complementary techniques showed a higher affinity of CPZ for PS headgroups, enhanced PS-mediated penetration in the membrane, and higher drug retention within the anionic lipid bilayer compared with POPC alone. At high concentration, CPZ induced the formation of mixed micelles on the surface of the treated membranes.