title: Development of a CP 31P NMR broadline simulation methodology for studying the interactions of antihypertensive AT1 antagonist losartan with phospholipid bilayers.
abstract: A cross-polarization (CP) (31)P NMR broadline simulation methodology was developed for studying the effects of drugs in phospholipids bilayers. Based on seven-parameter fittings, this methodology provided information concerning the conformational changes and dynamics effects of losartan in the polar region of the dipalmitoylphosphatidylcholine bilayers. The test molecule for this study was losartan, an antihypertensive drug known to exert its effect on AT(1) transmembrane receptors. The results were complemented and compared with those of differential scanning calorimetry, solid-state (13)C NMR spectroscopy, Raman spectroscopy, and electron spin resonance. More specifically, these physical chemical methodologies indicated that the amphipathic losartan molecule interacts with the hydrophilic-head zone of the lipid bilayers. The CP (31)P NMR broadline simulations showed that the lipid molecules in the bilayers containing losartan displayed greater collective tilt compared to the tilt displayed by the load-free bilayers, indicating improved packing. The Raman results displayed a decrease in the trans/gauche ratio and increased intermolecular interactions of the acyl chains in the liquid crystalline phase. Additional evidence, suggesting that losartan possibly anchors in the realm of the headgroup, was derived from upfield shift of the average chemical shift sigma(iso) of the (31)P signal in the presence of losartan and from shift of the observed peak at 715 cm(-1) attributed to C-N stretching in the Raman spectra.
authors.affiliation: Chemistry Department, University of Athens, Athens, Greece.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Fotakis
authors.forename: Dionisios
authors.initials: D
authors.lastname: Christodouleas
authors.forename: Petros
authors.initials: P
authors.lastname: Chatzigeorgiou
authors.forename: Maria
authors.initials: M
authors.lastname: Zervou
authors.forename: Nikolas-Ploutarch
authors.initials: NP
authors.lastname: Benetis
authors.forename: Kyriakos
authors.initials: K
authors.lastname: Viras
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry; D016880:Anisotropy; D002152:Calorimetry, Differential Scanning; D002247:Carbon Isotopes; D003198:Computer Simulation; D004578:Electron Spin Resonance Spectroscopy; D008051:Lipid Bilayers / Q000737:chemistry*; D019808:Losartan / Q000737:chemistry*; D008956:Models, Chemical; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D010759:Phosphorus Isotopes; D013059:Spectrum Analysis, Raman; D013696:Temperature
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D002247:Carbon Isotopes; D008051:Lipid Bilayers; D010759:Phosphorus Isotopes; D015060:1,2-Dipalmitoylphosphatidylcholine; D019808:Losartan