title: The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions. Comparative study with the AT1R antagonist drug olmesartan.
abstract: ΑΤ1 receptor (AT1R) antagonists exert their antihypertensive effects by preventing the vasoconstrictive hormone AngII to bind to the AT1 receptor. It has been proposed that these biological effects are mediated through a two-step mechanism reaction. In the first step, they are incorporated in the core of the lipid bilayers and in the second step they reach the active site of the receptor through lateral diffusion. In this model, drug/membrane interactions are key elements for the drugs achieving inhibition at the AT1 receptor. In this work, the interactions of the prodrug candesartan cilexetil (TCV-116) with lipid bilayers are studied at molecular detail. Solid-state (13)C-CP/MAS, 2D (1)H-(1)H NOESY NMR spectroscopy and in silico calculations are used. TCV-116 and olmesartan, another drug which acts as an AT1R antagonist are compared for their dynamic effects in lipid bilayers using solid-state (2)H-NMR. We find a similar localization of TCV-116 compared to other AT1 antagonists in the intermediate polar region. In addition, we can identify specific local interactions. These interactions may be associated in part with the discrete pharmacological profiles observed for different antagonists.
authors.affiliation: National and Kapodistrian University of Athens, Department of Chemistry, Panepistimioupolis Zografou 15771, Athens, Greece. Electronic address: doudaniotis@yahoo.gr.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Ntountaniotis
authors.affiliation: National and Kapodistrian University of Athens, Department of Chemistry, Panepistimioupolis Zografou 15771, Athens, Greece; University of Ioannina, Department of Chemistry, 45110 Ioannina, Greece.
authors.forename: Tahsin
authors.initials: T
authors.lastname: Kellici
authors.affiliation: University of Ioannina, Department of Chemistry, 45110 Ioannina, Greece.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzakos
authors.affiliation: University of Patras, Department of Chemistry, Patras 26500, Greece.
authors.forename: Pinelopi
authors.initials: P
authors.lastname: Kolokotroni
authors.affiliation: University of Patras, Department of Chemistry, Patras 26500, Greece.
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
authors.affiliation: Goethe University Frankfurt, Institute of Biophysical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Becker-Baldus
authors.affiliation: Goethe University Frankfurt, Institute of Biophysical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Glaubitz
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA.
authors.forename: Sonyan
authors.initials: S
authors.lastname: Lin
authors.affiliation: Northeastern University, Center for Drug Discovery, Boston, MA 02115, USA.
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
authors.affiliation: National and Kapodistrian University of Athens, Department of Chemistry, Panepistimioupolis Zografou 15771, Athens, Greece. Electronic address: tmavrom@chem.uoa.gr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry*; D001713:Biphenyl Compounds / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008567:Membranes, Artificial; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D013777:Tetrazoles / Q000737:chemistry*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D008567:Membranes, Artificial; D013777:Tetrazoles; C077793:candesartan cilexetil
keywords: Candesartan cilexetil (TCV-116); Drug/membrane interactions; In silico calculations; Lipid bilayers; Olmesartan; Solid-state NMR spectroscopy