{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:03:45Z","timestamp":1760238225163,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T00:00:00Z","timestamp":1595548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["18-14-00138"],"award-info":[{"award-number":["18-14-00138"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002674","name":"Russian Academy of Sciences","doi-asserted-by":"publisher","award":["\u201cPostgenomic technologies and promising solutions in biomedicine\u201d program"],"award-info":[{"award-number":["\u201cPostgenomic technologies and promising solutions in biomedicine\u201d program"]}],"id":[{"id":"10.13039\/501100002674","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002261","name":"Russian Foundation for Basic Research","doi-asserted-by":"publisher","award":["19-04-00350"],"award-info":[{"award-number":["19-04-00350"]}],"id":[{"id":"10.13039\/501100002261","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Basic Research Program at the National Research University Higher School of Economics and Russian Academic Excellence","award":["5-100"],"award-info":[{"award-number":["5-100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>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\u2013activity 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.<\/jats:p>","DOI":"10.3390\/ph13080163","type":"journal-article","created":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T11:16:35Z","timestamp":1595589395000},"page":"163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Sevanol and Its Analogues: Chemical Synthesis, Biological Effects and Molecular Docking"],"prefix":"10.3390","volume":"13","author":[{"given":"Olga A.","family":"Belozerova","sequence":"first","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6588-5012","authenticated-orcid":false,"given":"Dmitry I.","family":"Osmakov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrey","family":"Vladimirov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergey G.","family":"Koshelev","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1331-3949","authenticated-orcid":false,"given":"Anton O.","family":"Chugunov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"National Research University Higher School of Economics, 101000 Moscow, Russia"},{"name":"Moscow Institute of Physics and Technology (State University), Dolgoprudny, 141701 Moscow Oblast, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7628-0980","authenticated-orcid":false,"given":"Yaroslav A.","family":"Andreev","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor A.","family":"Palikov","sequence":"additional","affiliation":[{"name":"Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulia A.","family":"Palikova","sequence":"additional","affiliation":[{"name":"Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elvira R.","family":"Shaykhutdinova","sequence":"additional","affiliation":[{"name":"Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artem N.","family":"Gvozd","sequence":"additional","affiliation":[{"name":"Federal State Budgetary Institution \u00abScientific Center of Biomedical Technologies of Federal Medical and Biological Agency\u00bb (FSBI SCBT FMBA of Russia), 1 Svetlye Gory, Moscovskaya Oblast, 143442 Krasnogorskiy Rayon, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Igor A.","family":"Dyachenko","sequence":"additional","affiliation":[{"name":"Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 6 Nauki Avenue, 142290 Pushchino, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman G.","family":"Efremov","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"National Research University Higher School of Economics, 101000 Moscow, Russia"},{"name":"Moscow Institute of Physics and Technology (State University), Dolgoprudny, 141701 Moscow Oblast, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vadim S.","family":"Kublitski","sequence":"additional","affiliation":[{"name":"Shemyakin-Ovchinnikov Institute of 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Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+ Channel","volume":"67","author":"Kellenberger","year":"2015","journal-title":"Pharmacol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5496","DOI":"10.1523\/JNEUROSCI.23-13-05496.2003","article-title":"Acid-Sensing Ion Channel 1 Is Localized in Brain Regions with High Synaptic Density and Contributes to Fear Conditioning","volume":"23","author":"Wemmie","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/j.cell.2004.08.026","article-title":"Neuroprotection in Ischemia","volume":"118","author":"Xiong","year":"2004","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nn.3750","article-title":"Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity","volume":"17","author":"Kreple","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1038\/emboj.2008.213","article-title":"ASIC3, a sensor of acidic and primary inflammatory pain","volume":"27","author":"Deval","year":"2008","journal-title":"EMBO J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0304-3959(03)00269-0","article-title":"Chronic hyperalgesia induced by repeated acid injections in muscle is abolished by the loss of ASIC3, but not ASIC1","volume":"106","author":"Sluka","year":"2003","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1016\/S0896-6273(01)00547-5","article-title":"The DRASIC Cation Channel Contributes to the Detection of Cutaneous Touch and Acid Stimuli in Mice","volume":"32","author":"Price","year":"2001","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/nm.2844","article-title":"Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers","volume":"18","author":"Fromy","year":"2012","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20975","DOI":"10.1074\/jbc.272.34.20975","article-title":"Molecular Cloning of a Non-inactivating Proton-gated Na + Channel Specific for Sensory Neurons","volume":"272","author":"Waldmann","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.pain.2005.05.021","article-title":"Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels","volume":"117","author":"Lehto","year":"2005","journal-title":"Pain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8026","DOI":"10.1523\/JNEUROSCI.21-20-08026.2001","article-title":"Nonsteroid Anti-Inflammatory Drugs Inhibit Both the Activity and the Inflammation-Induced Expression of Acid-Sensing Ion Channels in Nociceptors","volume":"21","author":"Voilley","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/j.neuropharm.2010.01.011","article-title":"Diarylamidines: High potency inhibitors of acid-sensing ion channels","volume":"58","author":"Chen","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1124\/mol.117.110064","article-title":"Diminazene Is a Slow Pore Blocker of Acid-Sensing Ion Channel 1a (ASIC1a)","volume":"92","author":"Schmidt","year":"2017","journal-title":"Mol. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuropharm.2014.08.018","article-title":"Monoamine NMDA receptor channel blockers inhibit and potentiate native and recombinant proton-gated ion channels","volume":"89","author":"Tikhonova","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"25116","DOI":"10.1074\/jbc.M003643200","article-title":"Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na + Channels","volume":"275","author":"Escoubas","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3750","DOI":"10.1073\/pnas.1614728114","article-title":"Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a","volume":"114","author":"Chassagnon","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/nature11494","article-title":"Black mamba venom peptides target acid-sensing ion channels to abolish pain","volume":"490","author":"Diochot","year":"2012","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/nature10607","article-title":"A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain","volume":"479","author":"Bohlen","year":"2011","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1038\/sj.emboj.7600177","article-title":"A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons","volume":"23","author":"Diochot","year":"2004","journal-title":"EMBO J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"23116","DOI":"10.1074\/jbc.M113.485516","article-title":"Sea Anemone Peptide with Uncommon \u03b2-Hairpin Structure Inhibits Acid-sensing Ion Channel 3 (ASIC3) and Reveals Analgesic Activity","volume":"288","author":"Osmakov","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.peptides.2018.04.013","article-title":"New APETx-like peptides from sea anemone Heteractis crispa modulate ASIC1a channels","volume":"104","author":"Kalina","year":"2018","journal-title":"Peptides"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1134\/S1068162012060064","article-title":"A sea anemone polypeptide toxin inhibiting the ASIC3 acid-sensitive channel","volume":"38","author":"Kozlov","year":"2012","journal-title":"Russ. J. Bioorganic Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32993","DOI":"10.1074\/jbc.M112.366427","article-title":"Lignan from thyme possesses inhibitory effect on ASIC3 channel current","volume":"287","author":"Dubinnyi","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Andreev, Y., Osmakov, D., Koshelev, S., Maleeva, E., Logashina, Y., Palikov, V., Palikova, Y., Dyachenko, I., and Kozlov, S. (2018). Analgesic Activity of Acid-Sensing Ion Channel 3 (ASIC3) Inhibitors: Sea Anemones Peptides Ugr9-1 and APETx2 versus Low Molecular Weight Compounds. Mar. Drugs, 16.","DOI":"10.3390\/md16120500"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1134\/S1068162015050106","article-title":"Biological Activity of Sevanol and Its Analogues 1","volume":"41","author":"Osmakov","year":"2015","journal-title":"Russ. J. Bioorganic Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.tet.2018.02.005","article-title":"The total synthesis of sevanol, a novel lignan isolated from the thyme plant (Thymus armeniacus)","volume":"74","author":"Belozerova","year":"2018","journal-title":"Tetrahedron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1248\/cpb.59.502","article-title":"Structure\u2013Activity Relationship of Caffeoylquinic Acids on the Accelerating Activity on ATP Production","volume":"59","author":"Miyamae","year":"2011","journal-title":"Chem. Pharm. Bull. (Tokyo)."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9692","DOI":"10.1021\/jo801708q","article-title":"Total Synthesis of Citrafungin A","volume":"73","author":"Calo","year":"2008","journal-title":"J. Org. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1016\/j.tet.2019.06.033","article-title":"Isolation, total synthesis and quantification of caffeoylisocitric acid, a characteristic ingredient of the superfood amaranth","volume":"75","author":"Zhou","year":"2019","journal-title":"Tetrahedron"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1071\/CH09182","article-title":"Formal Total Synthesis of (+)-Citrafungin A","volume":"62","author":"Tsegay","year":"2009","journal-title":"Aust. J. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/cmdc.201200585","article-title":"Carboxylic Acid (Bio)Isosteres in Drug Design","volume":"8","author":"Ballatore","year":"2013","journal-title":"ChemMedChem"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3987\/COM-01-S(K)24","article-title":"Biomimetic Syntheses of Neurotrophic Americanol A and Isoamericanol A by Horseradish Peroxidase (HRP) Catalyzed Oxidative Coupling","volume":"56","author":"Fukuyama","year":"2002","journal-title":"Heterocycles"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0223-5234(88)90167-5","article-title":"Isocytosine H2-receptor histamine antagonists I. Oxmetidine and related compounds","volume":"23","author":"Brown","year":"1988","journal-title":"Eur. J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1074\/jbc.M705118200","article-title":"Endogenous arginine-phenylalanine-amide-related peptides alter steady-state desensitization of ASIC1a","volume":"283","author":"Sherwood","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Osmakov, D.I., Koshelev, S.G., Lyukmanova, E.N., Shulepko, M.A., Andreev, Y.A., Illes, P., and Kozlov, S.A. (2019). Multiple Modulation of Acid-Sensing Ion Channel 1a by the Alkaloid Daurisoline. Biomolecules, 9.","DOI":"10.3390\/biom9080336"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2599","DOI":"10.1038\/s41598-018-37426-5","article-title":"Mutations in the palm domain disrupt modulation of acid-sensing ion channel 1a currents by neuropeptides","volume":"9","author":"Bargeton","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.neuroscience.2017.02.025","article-title":"Quercetin inhibits acid-sensing ion channels through a putative binding site in the central vestibular region","volume":"348","author":"Mukhopadhyay","year":"2017","journal-title":"Neuroscience"},{"key":"ref_39","first-page":"597","article-title":"Animal models of nociception","volume":"53","author":"Gozariu","year":"2001","journal-title":"Pharmacol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1038\/nn1940","article-title":"A tarantula peptide against pain via ASIC1a channels and opioid mechanisms","volume":"10","author":"Mazzuca","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Osmakov, D.I., Koshelev, S.G., Palikov, V.A., Palikova, Y.A., Shaykhutdinova, E.R., Dyachenko, I.A., Andreev, Y.A., and Kozlov, S.A. (2019). Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties. Toxins, 11.","DOI":"10.3390\/toxins11090542"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"393","DOI":"10.2174\/092986707779941050","article-title":"Molecular Lipophilicity in Protein Modeling and Drug Design","volume":"14","author":"Efremov","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1146\/annurev.biophys.29.1.291","article-title":"Comparative Protein Structure Modeling of Genes and Genomes","volume":"29","author":"Stuart","year":"2000","journal-title":"Annu. Rev. Biophys. Biomol. Struct."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"W374","DOI":"10.1093\/nar\/gky380","article-title":"CavityPlus: A web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction","volume":"46","author":"Xu","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/8\/163\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:51:35Z","timestamp":1760176295000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/13\/8\/163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,24]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ph13080163"],"URL":"https:\/\/doi.org\/10.3390\/ph13080163","relation":{},"ISSN":["1424-8247"],"issn-type":[{"type":"electronic","value":"1424-8247"}],"subject":[],"published":{"date-parts":[[2020,7,24]]}}}