title: Comparative biophysical studies of sartan class drug molecules losartan and candesartan (CV-11974) with membrane bilayers.
abstract: The interactions of the antihypertensive AT(1) antagonists candesartan and losartan with membrane bilayers were studied through the application of DSC, Raman, and solid state (31)P NMR spectroscopies. (1)H and (13)C NMR resonances of candesartan were assigned on the basis of 1D and 2D NMR spectroscopy. A (31)P CP NMR broadline fitting methodology in combination with ab initio computations was implemented and, in conjunction with DSC and Raman results, provided valuable information regarding the perturbation, localization, orientation, and dynamic properties of the drugs in membrane models. In particular, results indicate that losartan anchors in the mesophase region of the lipid bilayers with the tetrazole group oriented toward the polar headgroup, whereas candesartan has less definite localization spanning from water interface toward the mesophase and upper segment of the hydrophobic region. Both sartan molecules decrease the mobilization of the phospholipids alkyl chains. Losartan exerts stronger interactions compared with candesartan, as depicted by the more prominent thermal, structural, and dipolar (1)H-(31)P changes that are caused in the lipid bilayers. At higher concentrations, candesartan strengthens the polar interactions and induces increased order at the bilayer surface. At the highest concentration used (20 mol %), only losartan induces formation of microdomains attributed to the flexibility of its alkyl chain. These results in correlation to reported data with other AT(1) antagonists strengthen the hypothesis that this class of molecules may approach the active site of the receptor by insertion in the lipid core, followed by lateral diffusion toward the binding site. Further, the similarities and differences of these drugs in their interactions with lipid bilayers establish, at least in part, their pharmacological properties.
authors.affiliation: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, Vas. Constantinou 48, Athens 11635, Greece.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Fotakis
authors.forename: Dionysios
authors.initials: D
authors.lastname: Christodouleas
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Zoumpoulakis
authors.forename: Eftichia
authors.initials: E
authors.lastname: Kritsi
authors.forename: Nikolas-Ploutarch
authors.initials: NP
authors.lastname: Benetis
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
authors.forename: Heribert
authors.initials: H
authors.lastname: Reis
authors.forename: Argiro
authors.initials: A
authors.lastname: Gili
authors.forename: Manthos G
authors.initials: MG
authors.lastname: Papadopoulos
authors.forename: Maria
authors.initials: M
authors.lastname: Zervou
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry*; D001713:Biphenyl Compounds; D002152:Calorimetry, Differential Scanning; D008051:Lipid Bilayers / Q000737:chemistry*; D019808:Losartan / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000378:metabolism; D012997:Solvents / Q000737:chemistry; D013059:Spectrum Analysis, Raman; D013777:Tetrazoles / Q000737:chemistry*
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D008051:Lipid Bilayers; D044140:Receptor, Angiotensin, Type 1; D012997:Solvents; D013777:Tetrazoles; D019808:Losartan; C081643:candesartan