{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T14:17:52Z","timestamp":1772806672383,"version":"3.50.1"},"reference-count":61,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 \u00b5M. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications.<\/jats:p>","DOI":"10.3390\/molecules27134133","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T01:48:38Z","timestamp":1656467318000},"page":"4133","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9382-337X","authenticated-orcid":false,"given":"Quentin","family":"Coquerel","sequence":"first","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Legendre","sequence":"additional","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3413-8732","authenticated-orcid":false,"given":"Jacinthe","family":"Frangieh","sequence":"additional","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"},{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, L\u2019institut du Thorax, 44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4236-6687","authenticated-orcid":false,"given":"Stephan","family":"Waard","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, L\u2019institut du Thorax, 44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5100-5571","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Montnach","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, L\u2019institut du Thorax, 44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4272-2784","authenticated-orcid":false,"given":"Leos","family":"Cmarko","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, L\u2019institut du Thorax, 44000 Nantes, France"},{"name":"Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 128 00 Prague, Czech Republic"},{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, 166 10 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Khoury","sequence":"additional","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"},{"name":"Laboratory of Applied Biotechnology, AZM Centre for Research in Biotechnology and Its Application, Doctoral School for Sciences and Technology, Tripoli 1352, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8953-0328","authenticated-orcid":false,"given":"Charifat","family":"Hassane","sequence":"additional","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"},{"name":"Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6477-9592","authenticated-orcid":false,"given":"Dimitri","family":"Br\u00e9ard","sequence":"additional","affiliation":[{"name":"Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Siegler","sequence":"additional","affiliation":[{"name":"Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6502-3110","authenticated-orcid":false,"given":"Ziad","family":"Fajloun","sequence":"additional","affiliation":[{"name":"Laboratory of Applied Biotechnology, AZM Centre for Research in Biotechnology and Its Application, Doctoral School for Sciences and Technology, Tripoli 1352, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harold","family":"De Pomyers","sequence":"additional","affiliation":[{"name":"Latoxan Laboratory, 26800 Portes l\u00e8s Valence, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamel","family":"Mabrouk","sequence":"additional","affiliation":[{"name":"CNRS, ICR, Aix Marseille Univ, 13397 Marseille, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0040-1109","authenticated-orcid":false,"given":"Norbert","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Third Faculty of Medicine, Charles University, Ruska 87, 10 034 Prague, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1094-0285","authenticated-orcid":false,"given":"Daniel","family":"Henrion","sequence":"additional","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pascal","family":"Richomme","sequence":"additional","affiliation":[{"name":"Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2214-2611","authenticated-orcid":false,"given":"C\u00e9sar","family":"Mattei","sequence":"additional","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2782-9615","authenticated-orcid":false,"given":"Michel","family":"Waard","sequence":"additional","affiliation":[{"name":"Nantes Universit\u00e9, CHU Nantes, CNRS, INSERM, L\u2019institut du Thorax, 44000 Nantes, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne-Marie","family":"Le Ray","sequence":"additional","affiliation":[{"name":"Univ Angers, SONAS, SFR QUASAV, 49100 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3346-7059","authenticated-orcid":false,"given":"Christian","family":"Legros","sequence":"additional","affiliation":[{"name":"Univ Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, 49000 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,28]]},"reference":[{"key":"ref_1","unstructured":"Hille, B. 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