Cargando…

Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking

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 the perception of inflammatory and neurological pain, making these cha...

Descripción completa

Detalles Bibliográficos
Autores principales: Belozerova, Olga A., Osmakov, Dmitry I., Vladimirov, Andrey, Koshelev, Sergey G., Chugunov, Anton O., Andreev, Yaroslav A., Palikov, Victor A., Palikova, Yulia A., Shaykhutdinova, Elvira R., Gvozd, Artem N., Dyachenko, Igor A., Efremov, Roman G., Kublitski, Vadim S., Kozlov, Sergey A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466040/
https://www.ncbi.nlm.nih.gov/pubmed/32722325
http://dx.doi.org/10.3390/ph13080163
_version_ 1783577721040797696
author Belozerova, Olga A.
Osmakov, Dmitry I.
Vladimirov, Andrey
Koshelev, Sergey G.
Chugunov, Anton O.
Andreev, Yaroslav A.
Palikov, Victor A.
Palikova, Yulia A.
Shaykhutdinova, Elvira R.
Gvozd, Artem N.
Dyachenko, Igor A.
Efremov, Roman G.
Kublitski, Vadim S.
Kozlov, Sergey A.
author_facet Belozerova, Olga A.
Osmakov, Dmitry I.
Vladimirov, Andrey
Koshelev, Sergey G.
Chugunov, Anton O.
Andreev, Yaroslav A.
Palikov, Victor A.
Palikova, Yulia A.
Shaykhutdinova, Elvira R.
Gvozd, Artem N.
Dyachenko, Igor A.
Efremov, Roman G.
Kublitski, Vadim S.
Kozlov, Sergey A.
author_sort Belozerova, Olga A.
collection PubMed
description 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 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 the 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 the carboxyl groups of the molecule. At the structural level, we predicted the presence of a 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. The 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 the invasive (i.v.) method, thus opening new horizons for medicinal uses of sevanol.
format Online
Article
Text
id pubmed-7466040
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-74660402020-09-14 Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking Belozerova, Olga A. Osmakov, Dmitry I. Vladimirov, Andrey Koshelev, Sergey G. Chugunov, Anton O. Andreev, Yaroslav A. Palikov, Victor A. Palikova, Yulia A. Shaykhutdinova, Elvira R. Gvozd, Artem N. Dyachenko, Igor A. Efremov, Roman G. Kublitski, Vadim S. Kozlov, Sergey A. Pharmaceuticals (Basel) Communication 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 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 the 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 the carboxyl groups of the molecule. At the structural level, we predicted the presence of a 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. The 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 the invasive (i.v.) method, thus opening new horizons for medicinal uses of sevanol. MDPI 2020-07-24 /pmc/articles/PMC7466040/ /pubmed/32722325 http://dx.doi.org/10.3390/ph13080163 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Communication
Belozerova, Olga A.
Osmakov, Dmitry I.
Vladimirov, Andrey
Koshelev, Sergey G.
Chugunov, Anton O.
Andreev, Yaroslav A.
Palikov, Victor A.
Palikova, Yulia A.
Shaykhutdinova, Elvira R.
Gvozd, Artem N.
Dyachenko, Igor A.
Efremov, Roman G.
Kublitski, Vadim S.
Kozlov, Sergey A.
Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking
title Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking
title_full Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking
title_fullStr Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking
title_full_unstemmed Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking
title_short Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking
title_sort sevanol and its analogues: chemical synthesis, biological effects and molecular docking
topic Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466040/
https://www.ncbi.nlm.nih.gov/pubmed/32722325
http://dx.doi.org/10.3390/ph13080163
work_keys_str_mv AT belozerovaolgaa sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT osmakovdmitryi sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT vladimirovandrey sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT koshelevsergeyg sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT chugunovantono sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT andreevyaroslava sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT palikovvictora sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT palikovayuliaa sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT shaykhutdinovaelvirar sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT gvozdartemn sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT dyachenkoigora sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT efremovromang sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT kublitskivadims sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking
AT kozlovsergeya sevanolanditsanalogueschemicalsynthesisbiologicaleffectsandmoleculardocking