{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T22:44:20Z","timestamp":1783550660022,"version":"3.55.0"},"reference-count":73,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:00:00Z","timestamp":1684713600000},"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":["23-73-00077"],"award-info":[{"award-number":["23-73-00077"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3H-1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5\u2032-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5\u2032-ethynyllappaconitine, followed by cyclocondensation with o-phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.<\/jats:p>","DOI":"10.3390\/molecules28104234","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T05:04:44Z","timestamp":1684731884000},"page":"4234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis, Pharmacological Evaluation, and Molecular Modeling of Lappaconitine\u20131,5-Benzodiazepine Hybrids"],"prefix":"10.3390","volume":"28","author":[{"given":"Kirill","family":"Cheremnykh","sequence":"first","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkadiy","family":"Bryzgalov","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1795-9256","authenticated-orcid":false,"given":"Dmitry","family":"Baev","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6415-5840","authenticated-orcid":false,"given":"Sergey","family":"Borisov","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia","family":"Sotnikova","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Savelyev","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Tolstikova","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamansur","family":"Sagdullaev","sequence":"additional","affiliation":[{"name":"S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Mirzo Ulugbek Str. 77, Tashkent 100170, Uzbekistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0761-9696","authenticated-orcid":false,"given":"Elvira","family":"Shults","sequence":"additional","affiliation":[{"name":"N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Lavrentjev Avenue 9, 630090 Novosibirsk, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/S0254-6272(09)60051-0","article-title":"Study of analgesic and anti-inflammatory effects of lappaconitine gelata","volume":"29","author":"Wang","year":"2009","journal-title":"J. Tradit. Chin. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Thawabteh, A.M., Thawabteh, A., Lelario, F., Bufo, S.A., and Scrano, L. (2021). Classification, Toxicity and Bioactivity of Natural Diterpenoid Alkaloids. Molecules, 26.","DOI":"10.3390\/molecules26134103"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1007\/s00213-018-4948-y","article-title":"Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression","volume":"235","author":"Sun","year":"2018","journal-title":"Psychopharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1016\/j.neuint.2011.01.016","article-title":"Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion","volume":"58","author":"Ou","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_5","first-page":"301","article-title":"Anti-inflammatory and analgesic activities of N-deacetyllappaconitine and lappaconitine","volume":"8","author":"Liu","year":"1987","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0021-5198(19)39736-7","article-title":"Pharmacological studies on lappaconitine: Possible interaction with endogenous noradrenergic and serotonergic pathways to induce antinociception","volume":"58","author":"Ono","year":"1992","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1007\/BF02291540","article-title":"Diterpenoid alkaloids as a new class of antiarrhythmic agents. Structure-activity relationship","volume":"33","author":"Dzhakhangirov","year":"1997","journal-title":"Chem. Nat. Compd."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0301-0082(98)00037-9","article-title":"The effects of Aconitum alkaloids on the central nervous system","volume":"56","author":"Ameri","year":"1998","journal-title":"Prog. Neurobiol."},{"key":"ref_9","first-page":"892","article-title":"Pharmacological studies of lappaconitine. Analgesic activities","volume":"38","author":"Ono","year":"1988","journal-title":"Arzneimittelforschung"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Li, X., Wang, X., Li, Z., Mao, Y., Liu, Z., Liu, X., Zhu, X., and Zhang, J. (2022). A Metabolomic study of the analgesic effect of lappaconitine hydrobromide (LAH) on inflammatory pain. Metabolites, 12.","DOI":"10.3390\/metabo12100923"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1055\/s-2006-957359","article-title":"Cardiac effects of lappaconitine and N-deacetyllappaconitine, two diterpenoid alkaloids from plants of the Aconitum and Delphinium species","volume":"64","author":"Heubach","year":"1998","journal-title":"Planta Med."},{"key":"ref_12","first-page":"39","article-title":"Mode of antinociceptive and toxic action of alkaloids of Aconitum species","volume":"357","author":"Guster","year":"1998","journal-title":"Naunyn Schmiedeberg\u2019s Arch. Pharmacol."},{"key":"ref_13","first-page":"201","article-title":"The effect of allapinine on the sodium currents of isolated trigeminal ganglion neurons and cardiomyocytes of rats","volume":"22","author":"Valeev","year":"1990","journal-title":"Neirofiziologiia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/S0014-2999(97)01268-5","article-title":"Aconitum sp. alkaloids: The modulation of voltage-dependent Na+ channels, toxicity and antinociceptive properties","volume":"337","author":"Friese","year":"1997","journal-title":"Eur. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1124\/mol.59.2.183","article-title":"Irreversible block of human heart (hH1) sodium channels by the plant alkaloid lappaconitine","volume":"59","author":"Wright","year":"2001","journal-title":"Mol. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1026219","DOI":"10.3389\/fphar.2022.1026219","article-title":"Processed lateral root of Aconitum carmichaelii Debx.: A review of cardiotonic effects and cardiotoxicity on molecular mechanisms","volume":"13","author":"Zhang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"48","DOI":"10.18565\/cardio.2016.3.48-53","article-title":"The study of evidence base for the use of lappaconitine hydrobromide in patients with atrial fibrillation","volume":"56","author":"Erlikh","year":"2016","journal-title":"Kardiologiia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41401-018-0067-x","article-title":"Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels","volume":"40","author":"Li","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1111\/bcpt.12178","article-title":"Natural products evaluated in neuropathic pain models\u2014A systematic review","volume":"114","author":"Quintans","year":"2014","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/jphp.12310","article-title":"A review on phytochemistry, pharmacology and toxicology studies of Aconitum","volume":"67","author":"Nyirimigabo","year":"2015","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"304","DOI":"10.2174\/1570193X14666170519143252","article-title":"Polypharmacology of Aconitum and Delphinium sp. Diterpene alkaloids: Antiarrhythmic, analgesic and anti-inflammatory effects","volume":"14","author":"Pereira","year":"2017","journal-title":"Mini Rev. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107698","DOI":"10.1016\/j.pharmthera.2020.107698","article-title":"Current state and future perspective of cardiovascular medicines derived from natural products","volume":"216","author":"Zhao","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_23","first-page":"505","article-title":"A systematic review of pharmacological activities, toxicological mechanisms and pharmacokinetic studies on Aconitum alkaloids","volume":"19","author":"Mi","year":"2021","journal-title":"Chin. J. Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"115317","DOI":"10.1016\/j.jep.2022.115317","article-title":"Traditional processing, uses, phytochemistry, pharmacology and toxicology of Aconitum sinomontanum Nakai: A comprehensive review","volume":"293","author":"Zhang","year":"2022","journal-title":"J. Ethnopharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s13181-022-00896-1","article-title":"Clinical effects from ingestion of lappaconitine, an Aconitum alkaloid with sodium channel blocking effects","volume":"18","author":"McCabe","year":"2022","journal-title":"J. Med. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12951-015-0107-3","article-title":"Nanostructured lipid carriers for percutaneous administration of alkaloids isolated from Aconitum sinomontanum","volume":"13","author":"Guo","year":"2015","journal-title":"J. Nanobiotech."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.alkal.2021.08.001","article-title":"The diterpenoid alkaloids","volume":"87","author":"Liu","year":"2022","journal-title":"Alkaloids Chem. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1111\/j.1472-8206.2004.00222.x","article-title":"The local anesthetic activity of aconitum alkaloids can be explained by their structural properties: A QSAR analysis","volume":"18","year":"2004","journal-title":"Fund. Clin. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1007\/s00044-015-1402-0","article-title":"Synthesis, characterization and antinociceptive properties of the lappaconitine salts","volume":"24","author":"Sun","year":"2015","journal-title":"Med. Chem. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1007\/s12264-021-00774-w","article-title":"Quantitative electrophysiological evaluation of the analgesic efficacy of two lappaconitine derivatives: A window into antinociceptive drug mechanisms","volume":"37","author":"Teng","year":"2021","journal-title":"Neurosci. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s00044-019-02346-0","article-title":"Lappaconitine sulfate induces apoptosis in human colon cancer HT-29 cells and downregulates PI3K\/AKT\/GSK3\u03b2 signaling pathway","volume":"28","author":"Qu","year":"2019","journal-title":"Med. Chem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1159\/000506081","article-title":"Lappaconitine sulfate inhibits proliferation and induces apoptosis in human hepatocellular carcinoma HepG2 cells through the reactive oxygen species-dependent mitochondrial pathway","volume":"105","author":"Zhang","year":"2020","journal-title":"Pharmacology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104699","DOI":"10.1016\/j.bioorg.2021.104699","article-title":"Synthesis and structure\u2013activity relationship of lipo\u2013diterpenoid alkaloids with potential target of topoisomerase II\u03b1 for breast cancer treatment","volume":"109","author":"Luan","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1248\/cpb.57.801","article-title":"Structure\u2013analgesic activity relationship studies on the C18- and C19-diterpenoid alkaloids","volume":"57","author":"Wang","year":"2009","journal-title":"Chem. Pharm. Bull."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112866","DOI":"10.1016\/j.phytochem.2021.112866","article-title":"Diterpenoid alkaloids from the whole herb of Delphinium grandiflorum L.","volume":"190","author":"Xu","year":"2021","journal-title":"Phytochemistry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1016\/j.apsb.2019.09.002","article-title":"Synthesis, in vitro and in vivo biological evaluation of novel lappaconitine derivatives as potential anti-inflammatory agents","volume":"10","author":"Pang","year":"2020","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"114776","DOI":"10.1016\/j.ejmech.2022.114776","article-title":"Design, synthesis, and biological evaluation of low-toxic lappaconitine derivatives as potential analgesics","volume":"243","author":"Li","year":"2022","journal-title":"Eur. J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"211","DOI":"10.2174\/18715257113119990083","article-title":"Lappaconitine: Influence of halogen substituent on the antiarrhythmic activity","volume":"11","author":"Bryzgalov","year":"2013","journal-title":"Cardiovasc. Hematol. Agents Med. Chem."},{"key":"ref_39","first-page":"599","article-title":"Effect of the structure of lappaconitine derivatives on antiarrhythmic activity","volume":"15","author":"Tolstikova","year":"2007","journal-title":"Chem. Sustain. Dev."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Cheremnykh, K.P., Savelyev, V.A., Borisov, S.A., Ivanov, I.D., Baev, D.S., Tolstikova, T.G., and Vavilin, V.A. (2020). Hybrides of alkaloid lappaconitine with pyrimidine motif on the anthranilic acid moiety: Design, synthesis, and investigation of antinociceptive potency. Molecules, 25.","DOI":"10.3390\/molecules25235578"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3694","DOI":"10.1039\/D2RA06045K","article-title":"Synthetic aspects of 1,4- and 1,5-benzodiazepines using o-phenylenediamine: A study of past quinquennial","volume":"13","author":"Teli","year":"2023","journal-title":"RSC Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"103668","DOI":"10.1016\/j.bioorg.2020.103668","article-title":"Recent advances in synthesis and medicinal chemistry of benzodiazepines","volume":"97","author":"Arora","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4796","DOI":"10.1002\/ejoc.200800619","article-title":"Three-component synthesis of cryofluorescent 2,4-disubstituted 3H-1,5-benzodiazepines. Conformational control of emission properties","volume":"2008","author":"Willy","year":"2008","journal-title":"Eur. J. Org. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Albano, G., and Aronica, L.A. (2020). Acyl Sonogashira cross-coupling: State of the art and application to the synthesis of heterocyclic compounds. Catalyst, 10.","DOI":"10.3390\/catal10010025"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Niedballa, J., and M\u00fcller, T.J.J. (2022). Heterocycles by Consecutive Multicomponent Syntheses via Catalytically Generated Alkynoyl Intermediates. Catalyst, 12.","DOI":"10.3390\/catal12010090"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1007\/s11172-007-0191-0","article-title":"Study of alkaloids of the Siberian and Altai flora 14. Synthesis of alkaloid-based tertiary N-(3-arylprop-2-ynyl)amines","volume":"56","author":"Osadchii","year":"2007","journal-title":"Russ. Chem. Bull."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s00044-019-02314-8","article-title":"Design, synthesis, cytotoxicity, and molecular modeling study of 2,4,6-trisubstituted pyrimidines with anthranilate ester moiety","volume":"28","author":"Cheremnykh","year":"2019","journal-title":"Med. Chem. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1002\/ajoc.202100474","article-title":"An efficient access to 3,5-disubstituted isoxazoles with anthranilate ester moiety: Alkaloid lappaconitine\u2013aryl conjugates with an isoxazole linker","volume":"10","author":"Cheremnykh","year":"2021","journal-title":"Asian J. Org. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1134\/S0012500807100059","article-title":"Study of alkaloids of the flora of Siberia and Altai: Synthesis of bivalent ligands of the aconitane type","volume":"416","author":"Osadchii","year":"2007","journal-title":"Dokl. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/BF00807594","article-title":"Study of the conformational equilibria of some 2-(2\u2032-hydroxyphenyl)-4-aryl-3H-1,5-benzodiazepines using 1H, 13C, and 15N NMR spectroscopy","volume":"128","author":"Ahmad","year":"1997","journal-title":"Mon. Chem."},{"key":"ref_51","first-page":"412","article-title":"Acetic acid for analgesic screening","volume":"18","author":"Koster","year":"1959","journal-title":"Fed. Proc."},{"key":"ref_52","first-page":"385","article-title":"Synthetic analgesics. II. Dithienylbutenyl- and dithienylbutylamines","volume":"107","author":"Eddy","year":"1953","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_53","first-page":"597","article-title":"Animal models of nociception","volume":"53","author":"Gozariu","year":"2001","journal-title":"Pharm. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.tcm.2010.03.002","article-title":"Sodium channel molecular conformations and antiarrhythmic drug affinity","volume":"20","author":"Sheets","year":"2010","journal-title":"Trends Cardiovas. Med."},{"key":"ref_55","first-page":"1355","article-title":"Potassium channel openers and blockers: Do they possess proarrhythmic or antiarrhythmic activity in ischemic and reperfused rat hearts?","volume":"267","author":"Tosaki","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"114413","DOI":"10.1016\/j.biopha.2023.114413","article-title":"Pharmacological mechanism of natural drugs and their active ingredients in the treatment of arrhythmia via calcium channel regulation","volume":"160","author":"Zhang","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_57","first-page":"314","article-title":"Physiological and pathophysiological insights of Nav1.4 and Nav1.5 comparison","volume":"6","author":"Loussouarn","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.bcp.2019.01.018","article-title":"Mining the Nav1.7 interactome: Opportunities for chronic pain therapeutics","volume":"163","author":"Chew","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.biopsych.2020.09.022","article-title":"Sex differences in nociceptor translatomes contribute to divergent prostaglandin signaling in male and female mice","volume":"91","author":"Ray","year":"2022","journal-title":"Biol. Psychiatry"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cell.2019.11.041","article-title":"Structure of the cardiac sodium channel","volume":"180","author":"Jiang","year":"2020","journal-title":"Cell"},{"key":"ref_61","first-page":"1","article-title":"Antiarrhythmic drugs. Part 1: An overview","volume":"14","author":"Sampson","year":"2019","journal-title":"Br. J. Cardiac. Nurs."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"841","DOI":"10.2174\/1568026621666210525105359","article-title":"Development of allosteric modulators of voltage-gated Na+ channels: A novel approach for an old target","volume":"21","author":"Dvorak","year":"2021","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"11474","DOI":"10.1002\/anie.202102196","article-title":"Structural basis for pore blockade of the human cardiac sodium channel Nav1.5 by the antiarrhythmic drug quinidine","volume":"60","author":"Li","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Mazola, Y., M\u00e1rquez Montesinos, J.C.E., Ram\u00edrez, D., Z\u00fa\u00f1iga, L., Decher, N., Ravens, U., Yarov-Yarovoy, V., and Gonz\u00e1lez, W. (2022). Common structural pattern for flecainide binding in atrial-selective Kv1.5 and Nav1.5 channels: A computational approach. Pharmaceutics, 14.","DOI":"10.20944\/preprints202205.0392.v1"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/BF00563771","article-title":"Karacoline\u2014A new diterpene alkaloid from Aconitum karacolicum","volume":"8","author":"Sultankhodzhaev","year":"1972","journal-title":"Chem. Nat. Compd."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jpba.2017.01.003","article-title":"Assessment of in vitro cardiotoxicity of extract fractions and diterpene alkaloids from Aconitum leucostomum Worosch: A short communication","volume":"137","author":"Nie","year":"2017","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.1023\/B:RUCB.0000012375.59390.38","article-title":"Study of alkaloids of the Siberian and Altai flora. 10. Synthesis of N(20)-deethyllappaconitine derivatives","volume":"52","author":"Pankrushina","year":"2003","journal-title":"Russ. Chem. Bull. Int. Ed."},{"key":"ref_68","unstructured":"(2020). Schrodinger Small Molecule Drug Discovery Suite, Schr\u00f6dinger, LLC."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: Improving force field accuracy on challenging regimes of chemical space","volume":"17","author":"Lu","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1021\/jm050540c","article-title":"Novel procedure for modeling ligand\/receptor induced fit effects","volume":"49","author":"Sherman","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein\u2013ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/prot.10613","article-title":"A Hierarchical approach to all-atom protein loop prediction","volume":"55","author":"Jacobson","year":"2004","journal-title":"Proteins Struct. Funct. 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