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Sevanol and its analogues: chemical synthesis, biological effects and molecular docking
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  • Olga Belozerova,
  • Dmitry Osmakov,
  • Andrey Vladimirov,
  • Sergey Koshelev,
  • Anton Chugunov,
  • Yaroslav Andreev,
  • Viktor Palikov,
  • Yulia Palikova,
  • Elvira Shaykhutdinova,
  • Artem Gvozd,
  • Igor Dyachenko,
  • Roman Efremov,
  • Vadim Kublitski,
  • Sergey Kozlov
Olga Belozerova
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Dmitry Osmakov
Institut bioorganiceskoj himii RAN
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Andrey Vladimirov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Sergey Koshelev
Institut bioorganiceskoj himii RAN
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Anton Chugunov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Yaroslav Andreev
Institut bioorganiceskoj himii RAN
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Viktor Palikov
Pushchino Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Yulia Palikova
Pushchino Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Elvira Shaykhutdinova
Pushchino Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Artem Gvozd
FMBA Rossii
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Igor Dyachenko
Pushchino Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Roman Efremov
Institut bioorganiceskoj himii RAN
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Vadim Kublitski
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Sergey Kozlov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences
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Abstract

Among acid-sensing ion channels (ASICs), ASIC1a and ASIC3 subunits are the most widespread and prevalent in physiological and pathophysiological conditions. They participate in synaptic plasticity, learning and memory as well as in the perception of inflammatory and neurological pain, making these channels attractive pharmacological targets. Sevanol, a natural lignan isolated from Thymus armeniacus, inhibits the activity of ASIC1a and ASIC3 isoforms and has a significant analgesic and anti-inflammatory effect. In this work, we described the efficient chemical synthesis scheme of sevanol and its analogues, which allows us to analyze the structure-activity relationships of different parts of this molecule. We found that the inhibitory activity of sevanol and its analogues on ASIC1a and ASIC3 channels depends on the number and availability of carboxyl groups of the molecule. At the structural level, we predicted the presence of sevanol binding site based on the presence of molecular docking in the central vestibule of the ASIC1a channel. We predicted that this site could also be occupied in part by the FRRF-amide peptide, and the competition assay of sevanol with this peptide confirmed this prediction. Intravenous (i.v.), intranasal (i.n.) and, especially, oral (p.o.) administration of synthetic sevanol in animal models produced significant analgesic and anti-inflammatory effects. Both non-invasive methods of sevanol administration (i.n. and p.o.) showed greater efficacy than invasive (i.v.) one, thus opening new horizons for medicinal uses of sevanol.

Peer review status:Published

24 Jul 2020Published in Pharmaceuticals volume 13 issue 8 on pages 163. 10.3390/ph13080163