Chlorpromazine interaction with glycerophospholipid liposomes studied by magic angle spinning solid state 13C-NMR and differential scanning calorimetry

Abstract

Phosphatidylserine (PS) extracted from pig brain and synthetic dipalmitoylphosphatidylcholine (DPPC) and dimyristoylphosphatidylcholine (DMPC) were used to make DPPC/DMPC and DPPC/PS large unilamellar liposomes with a diameter of approximately 1 microm. Chlorpromazine-HCl (CPZ), an amphipathic cationic psychotropic drug of the phenothiazine group, is known to partition into lipid bilayer membranes of liposomes with partition coefficients depending on the acyl chain length and to alter the bilayer structure in a manner depending on the phospholipid headgroups. The effects of adding CPZ to these membranes were studied by differential scanning calorimetry and proton cross polarization solid state magic angle spinning (13)C-nuclear magnetic resonance spectroscopy (CP-MAS-(13)C-NMR). CP-MAS-(13)C-NMR spectra of the DPPC (60%)/DMPC (40%) and the DPPC (54%)/DMPC (36%)/CPZ (10%) liposomes, show that CPZ has low or no interaction with the phospholipids of this neutral and densely packed bilayer. Conversely, the DPPC (54%)/PS (36%)/CPZ (10%) bilayer at 25 degrees C demonstrates interaction of CPZ with the phospholipid headgroups (PS). This CPZ interaction causes about 30% of the acyl chains to enter the gauche conformation with low or no CPZ interdigitation among the acyl chains at this temperature (25 degrees C). The DPPC (54%)/PS (36%)/CPZ (10%) bilayer at a sample temperature of 37 degrees C (T(C)=31.2 degrees C), shows CPZ interdigitation among the phospholipids as deduced from the finding that approximately 30% of the phospholipid acyl chains carbon resonances shift low-field by 5-15 ppm.

Importance of polyunsaturated acyl chains in chlorpromazine interaction with phosphatidylserines: A 13C and 31P solid-state NMR study

“…In micromolar concentration CPZ causes large increases in the mean molecular areas in monolayers of acidic phospholipids, whereas no such molecular area increase is found for the neutral glycerophospholipids in monolayers [16]. Similar findings by us [17], using magic angle spinning solid state 13 C NMR on bilayer samples with partial hydration (12 H 2 O per phospholipid), showed that CPZ had low or no interaction on the acyl packing of liposomes made of phospholipids without a net negative head group charge and with saturated acyl chains, such as palmitoyl (DPPC) and myristoyl (DMPC), while it caused a large (5-15 ppm) shift to higher ppm values of¨30% of the acyl chain carbon resonances in liposomes composed of pig brain PS (PBPS) and DPPC. PS is a major anionic phospholipid in mammalian cell membranes like peripheral and central nervous system myelin and PBPS was subjected to CPZ interaction studies as PBPS bilayer and in a mixture with DPPC as a DPPC (60 mol%)/PBPS (40 mol%) bilayer.…”

The Interaction of Peripheral Proteins and Membranes Studied with α-Lactalbumin and Phospholipid Bilayers of Various Compositions

“…Electron microscopy revealed that SUV were unilamellar. Large unilamellar vesicles (LUV) (ϳ1 m diameter) were prepared by extrusion as described (32).…”

Confocal Raman microscopy for simultaneous monitoring of partitioning and disordering of tricyclic antidepressants in phospholipid vesicle membranes

“…For instance, using a fluorescence depolarization membrane probe, nortriptyline and protriptyline were observed to have similar disordering effects on lipid T m in mixed liposomes composed of DPPC and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), but no effect could be seen in pure DPPC liposomes at 100 µM drug. [65] The TCAs amitriptyline, nortriptyline, imipramine, and desipramine were shown by calorimetry to have similarly lowered dipalmitoyllecithin lipid T m at 1 : 1 drug : lipid molar ratios, but the extra methyl group on imipramine and amitriptyline caused a multiphase thermal profile. [66] In contrast, another fluorescence study found that amitriptyline and nortriptyline had a greater lipid disordering effect than imipramine and desipramine in 1,2-dimyristoylsn-glycero-3-phosphocholine (DMPC), DMPC/cholesterol, and synaptosomal membranes (including effects on ATPase activity), but there was no apparent difference between amitriptyline and nortriptyline.…”