Thio-ether functionalized glycolipid amphiphilic compounds reveal a potent activator of SK3 channel with vasorelaxation effect - Université de Bretagne Occidentale Access content directly
Journal Articles Organic & Biomolecular Chemistry Year : 2021

Thio-ether functionalized glycolipid amphiphilic compounds reveal a potent activator of SK3 channel with vasorelaxation effect

Abstract

The modulation of SK3 ion channels can be efficiently and selectively achieved by using the amphiphilic compound Ohmline (a glyco-glycero-ether-lipid). We report herein a series of Ohmline analogues featuring the replacement of one ether function by a thioether function located at the same position or shifted close to its initial position. The variation of the lipid chain length and the preparation of two analogues featuring either one sulfoxide or one sulfone moiety complete this series. Patch clamp measurements indicate that the presence of the thioether function (compounds 7 and 17a) produces strong activators of SK3 channels, whereas the introduction of a sulfoxide or a sulfone function at the same place produces amphiphiles devoid of an effect on SK3 channels. Compounds 7 and 17a are the first amphiphilic compounds featuring strong activation of SK3 channels (close to 200% activation). The cytosolic calcium concentration determined from fluorescence at 3 different times for compound 7b (13 min, 1 h, 24 h) revealed that the effect is different suggesting that the compound could be metabolized over time. This compound could be used as a strong SK3 activator for a short time. The capacity of 7b to activate SK3 was then used to induce vasorelaxation via an endothelium-derived hyperpolarization (EDH) pathway. For the first time, we report that an amphiphilic compound can affect the endothelium dependent vasorelaxation.
Des analogues de l’Ohmline, contenant une fonction soufrée, sont décrits et testés comme modulateur des canaux ioniques SK3. Deux puissants activateurs sont identifiés. Néanmoins leur effet est limité dans le temps. Il est suggéré que ces composés, dotés d’une fonction thioéther, soient oxydés en sulfoxide et sulfone au cours du temps conduisant à une modification de leur activité. Un compose inhibiteur est également identifié mais son manque de sélectivité pourrait expliquer l’absence d’effet sur les entrées calciques associé à l’inhibition des canaux SK3. Finalement, il est montré pour la première fois qu’un composé amphiphile (l’un des activateurs des canaux SK3) présente un effet de vasorelaxation.
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Dates and versions

hal-03187829 , version 1 (01-04-2021)

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Charlotte Sevrain, Delphine Fontaine, Alicia Bauduin, Maxime Guéguinou, Bei Li Zhang, et al.. Thio-ether functionalized glycolipid amphiphilic compounds reveal a potent activator of SK3 channel with vasorelaxation effect. Organic & Biomolecular Chemistry, 2021, 19 (12), pp.2753-2766. ⟨10.1039/D1OB00021G⟩. ⟨hal-03187829⟩
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