Τίτλος:
The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions. Comparative study with the AT1R antagonist drug olmesartan
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
AT1 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 13C-CP/MAS, 2D 1H-1H 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 2H-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. © 2014 Elsevier B.V. All rights reserved.
Συγγραφείς:
Ntountaniotis, D.
Kellici, T.
Tzakos, A.
Kolokotroni, P.
Tselios, T.
Becker-Baldus, J.
Glaubitz, C.
Lin, S.
Makriyannis, A.
Mavromoustakos, T.
Περιοδικό:
Biochimica et Biophysica Acta. Biomembranes
Λέξεις-κλειδιά:
angiotensin 1 receptor; candesartan; candesartan hexetil; carbon 13; cholesterol; olmesartan, article; carbon nuclear magnetic resonance; comparative study; crystal structure; diffusion; drug receptor binding; drug structure; electric field; enzyme active site; isomerization; lipid bilayer; mass spectrometry; molecular dynamics; nuclear magnetic resonance spectroscopy; nuclear Overhauser effect; partition coefficient; phase transition; priority journal; proton nuclear magnetic resonance; solid state, Candesartan cilexetil (TCV-116); Drug/membrane interactions; In silico calculations; Lipid bilayers; Olmesartan; Solid-state NMR spectroscopy, Angiotensin II Type 1 Receptor Blockers; Benzimidazoles; Biphenyl Compounds; Humans; Magnetic Resonance Spectroscopy; Membranes, Artificial; Models, Chemical; Molecular Dynamics Simulation; Tetrazoles
DOI:
10.1016/j.bbamem.2014.06.003
