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  • The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions. Comparative study with the AT1R antagonist drug olmesartan.

The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions. Comparative study with the AT1R antagonist drug olmesartan.

Biochimica et biophysica acta (2014-06-20)
Dimitrios Ntountaniotis, Tahsin Kellici, Andreas Tzakos, Pinelopi Kolokotroni, Theodore Tselios, Johanna Becker-Baldus, Clemens Glaubitz, Sonyan Lin, Alexandros Makriyannis, Thomas Mavromoustakos
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.

MATERIALS
Product Number
Brand
Product Description

Candesartan cilexetil for peak identification, European Pharmacopoeia (EP) Reference Standard
Candesartan cilexetil for system suitability, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Deuterium, 99.8 atom % D
Sigma-Aldrich
Deuterium hydride, extent of labeling: 96 mol% DH, 98 atom % D
Sigma-Aldrich
Deuterium, 99.9 atom % D
SAFC
Cholesterol, Plant-Derived, SyntheChol®, NF, Ph. Eur., JP
Sigma-Aldrich
Deuterium, 99.96 atom % D
Sigma-Aldrich
SyntheChol® NS0 Supplement, 500 ×, synthetic cholesterol, animal component-free, sterile-filtered, aqueous solution, suitable for cell culture
Supelco
Cholesterol solution, certified reference material, 10 mg/mL in chloroform
Sigma-Aldrich
Cholesterol, from sheep wool, ≥92.5% (GC), powder
Sigma-Aldrich
Cholesterol, powder, BioReagent, suitable for cell culture, ≥99%
Sigma-Aldrich
Cholesterol, Sigma Grade, ≥99%
Sigma-Aldrich
Candesartan cilexetil, ≥98% (HPLC)
Supelco
Cholesterol, Pharmaceutical Secondary Standard; Certified Reference Material
Candesartan cilexetil, European Pharmacopoeia (EP) Reference Standard
SAFC
Cholesterol, from sheep wool, Controlled origin, meets USP/NF testing specifications