The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions. Comparative study with the AT1R antagonist drug olmesartan |
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Authors: | Dimitrios Ntountaniotis Tahsin Kellici Andreas Tzakos Pinelopi Kolokotroni Theodore Tselios Johanna Becker-Baldus Clemens Glaubitz Sonyan Lin Alexandros Makriyannis Thomas Mavromoustakos |
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Institution: | 1. National and Kapodistrian University of Athens, Department of Chemistry, Panepistimioupolis Zografou 15771, Athens, Greece;2. University of Ioannina, Department of Chemistry, 45110 Ioannina, Greece;3. University of Patras, Department of Chemistry, Patras 26500, Greece;4. Goethe University Frankfurt, Institute of Biophysical Chemistry, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany;5. University of Connecticut, School of Pharmacy, Storrs, CT 06269, USA;6. Northeastern University, Center for Drug Discovery, Boston, MA 02115, USA |
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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 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. |
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Keywords: | Candesartan cilexetil (TCV-116) Olmesartan Lipid bilayers Solid-state NMR spectroscopy In silico calculations Drug/membrane interactions |
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