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

Abstract

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.

Rational Drug Design and Synthesis of Molecules Targeting the Angiotensin II Type 1 and Type 2 Receptors

“…The data suggest that each AT 1 R antagonist has a unique action on the membrane [95,96,97,98,99,100,101,102,103,104,105,106,107]. In the following figure, the interactions of candesartan cilexetil and olmesartan are illustrated as revealed from a combination of NMR spectroscopy, molecular modeling, Raman spectroscopy and Differential Scanning Calorimetry [108]. The study of the mechanism of losartan as it embeds in the lipid bilayers and approaches the AT 1 R has been recently studied [109].…”

On the Rational Drug Design for Hypertension through NMR Spectroscopy

“…Similar spectra can be also obtained for other labeling schemes at different positions and thus this could reveal the selectivity of the drug to participate in specific topographic position in DPPC bilayers. In addition, comparative studies with other prodrugs or AT1R antagonists can be established using specific deuteration [45].…”

“…2 H solid-state NMR spectra were recorded on a BrukerAvance 600 MHz WB spectrometer equipped with a 4 mm HX double resonance MAS probe. Spectra were recorded without spinning the 4 mm MAS rotor using a solid echo sequence with an echo delay of 35 µs and a pulse length of 2.5 µs [45]. Reprinted from Biochimica et Biophysica Acta (BBA)-Biomembranes, 1838, Dimitrios Ntountaniotis, Tahsin Kellici, Andreas Tzakos, Pinelopi Kolokotroni, Theodore Tselios, Johanna Becker-Baldus, Clemens Glaubitz, Sonyan Lin, Alexandros Makriyannis, Thomas Mavromoustakos, The application of solid-state NMR spectroscopy to study candesartan cilexetil (TCV-116) membrane interactions.…”

Host–Guest Interactions between Candesartan and Its Prodrug Candesartan Cilexetil in Complex with 2-Hydroxypropyl-β-cyclodextrin: On the Biological Potency for Angiotensin II Antagonism

“…The possibility of the drug to act through both mechanisms can be also considered. We have previously studied the effects of various sartans on lipid bilayers. − These investigations combined several complementary biophysical techniques [differential scanning calorimetry (DSC), Raman spectroscopy, small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS), solid-state nuclear magnetic resonance (ssNMR), and molecular dynamics (MD) simulations] to reveal the complexity of the interaction of AT1 antagonists, when all of them were accommodated in the polar–nonpolar interface of the lipid bilayers. Each sartan is characterized by a unique “fingerprint” in terms of perturbation, orientation, and localization in lipid bilayers.…”