Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> Channels
The isoquinoline alkaloids (IAs) represent a large and diverse subfamily of phytochemicals in terms of structures and pharmacological activities, including ion channel inhibition. Several IAs, such as liriodenine (an oxoaporphine) and curine (a bisbenzylisoquinoline (BBIQ), inhibit the L-type voltag...
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MDPI AG
2022-06-01
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| Series: | Future Pharmacology |
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| Online Access: | https://www.mdpi.com/2673-9879/2/3/16 |
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| author | Jacinthe Frangieh Claire Legendre Dimitri Bréard Pascal Richomme Daniel Henrion Ziad Fajloun César Mattei Anne-Marie Le Ray Christian Legros |
| author_facet | Jacinthe Frangieh Claire Legendre Dimitri Bréard Pascal Richomme Daniel Henrion Ziad Fajloun César Mattei Anne-Marie Le Ray Christian Legros |
| author_sort | Jacinthe Frangieh |
| collection | DOAJ |
| description | The isoquinoline alkaloids (IAs) represent a large and diverse subfamily of phytochemicals in terms of structures and pharmacological activities, including ion channel inhibition. Several IAs, such as liriodenine (an oxoaporphine) and curine (a bisbenzylisoquinoline (BBIQ), inhibit the L-type voltage-gated Ca<sup>2+</sup> channels (LTCC). In this study, we aimed to search for new blockers of LTCC, which are therapeutic targets in neurological and cardiovascular diseases. We set up a screening assay using the rat pituitary GH3b6 cell line, which expresses two LTCC isoforms, Ca<sub>V</sub>1.2 and Ca<sub>V</sub>1.3. Both LTCC subtypes can be indirectly activated by KCl concentration elevation or directly by the dihydropyridine (DHP), BAY K8644, leading to an increase in the intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>). These Ca<sup>2+</sup> responses were completely blocked by the selective LTCC DHP inhibitor, nifedipine. Thereby, 16 selected IAs were tested for their ability to inhibit KCl and BAY K8644-induced Ca<sup>2+</sup> responses. We then identified three new potent LTCC blockers, namely, oxostephanine, thaliphyline, and thalmiculine. They inhibited LTCC with IC<sub>50</sub> values in the micromolar range through interaction to a binding site different to that of dihydropyridines. The two subfamilies of IAs, oxoaporphine with oxostephanine, and BBIQs with both thalyphilline and thalmiculine, constitute interesting pharmacophores for the development of future therapeutic leads for neurological and cardiovascular diseases. |
| first_indexed | 2024-03-09T18:19:29Z |
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| institution | Directory Open Access Journal |
| issn | 2673-9879 |
| language | English |
| last_indexed | 2024-03-09T18:19:29Z |
| publishDate | 2022-06-01 |
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| record_format | Article |
| series | Future Pharmacology |
| spelling | doaj.art-43c57006fac940fa92c0ad04aeb47dbd2023-11-24T08:25:37ZengMDPI AGFuture Pharmacology2673-98792022-06-012323825510.3390/futurepharmacol2030016Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> ChannelsJacinthe Frangieh0Claire Legendre1Dimitri Bréard2Pascal Richomme3Daniel Henrion4Ziad Fajloun5César Mattei6Anne-Marie Le Ray7Christian Legros8University of Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, F-49000 Angers, FranceUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, F-49000 Angers, FranceLaboratory of Applied Biotechnology, AZM Centre for Research in Biotechnology and its Application, Doctoral School for Sciences and Technology, Tripoli 1300, LebanonUniversity of Angers, INSERM, CNRS, MITOVASC, Equipe CarME, SFR ICAT, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceUniversity of Angers, SONAS, SFR QUASAV, F-49000 Angers, FranceThe isoquinoline alkaloids (IAs) represent a large and diverse subfamily of phytochemicals in terms of structures and pharmacological activities, including ion channel inhibition. Several IAs, such as liriodenine (an oxoaporphine) and curine (a bisbenzylisoquinoline (BBIQ), inhibit the L-type voltage-gated Ca<sup>2+</sup> channels (LTCC). In this study, we aimed to search for new blockers of LTCC, which are therapeutic targets in neurological and cardiovascular diseases. We set up a screening assay using the rat pituitary GH3b6 cell line, which expresses two LTCC isoforms, Ca<sub>V</sub>1.2 and Ca<sub>V</sub>1.3. Both LTCC subtypes can be indirectly activated by KCl concentration elevation or directly by the dihydropyridine (DHP), BAY K8644, leading to an increase in the intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>). These Ca<sup>2+</sup> responses were completely blocked by the selective LTCC DHP inhibitor, nifedipine. Thereby, 16 selected IAs were tested for their ability to inhibit KCl and BAY K8644-induced Ca<sup>2+</sup> responses. We then identified three new potent LTCC blockers, namely, oxostephanine, thaliphyline, and thalmiculine. They inhibited LTCC with IC<sub>50</sub> values in the micromolar range through interaction to a binding site different to that of dihydropyridines. The two subfamilies of IAs, oxoaporphine with oxostephanine, and BBIQs with both thalyphilline and thalmiculine, constitute interesting pharmacophores for the development of future therapeutic leads for neurological and cardiovascular diseases.https://www.mdpi.com/2673-9879/2/3/16isoquinoline alkaloidsL-type voltage-gated Ca<sup>2+</sup> channelsintracellular Ca<sup>2+</sup> measurementFura-2 fluorescent probeGH3b6 cells |
| spellingShingle | Jacinthe Frangieh Claire Legendre Dimitri Bréard Pascal Richomme Daniel Henrion Ziad Fajloun César Mattei Anne-Marie Le Ray Christian Legros Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> Channels Future Pharmacology isoquinoline alkaloids L-type voltage-gated Ca<sup>2+</sup> channels intracellular Ca<sup>2+</sup> measurement Fura-2 fluorescent probe GH3b6 cells |
| title | Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> Channels |
| title_full | Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> Channels |
| title_fullStr | Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> Channels |
| title_full_unstemmed | Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> Channels |
| title_short | Oxostephanine, Thalmiculine, and Thaliphyline—Three Isoquinoleine Alkaloids That Inhibit L-Type Voltage-Gated Ca<sup>2+</sup> Channels |
| title_sort | oxostephanine thalmiculine and thaliphyline three isoquinoleine alkaloids that inhibit l type voltage gated ca sup 2 sup channels |
| topic | isoquinoline alkaloids L-type voltage-gated Ca<sup>2+</sup> channels intracellular Ca<sup>2+</sup> measurement Fura-2 fluorescent probe GH3b6 cells |
| url | https://www.mdpi.com/2673-9879/2/3/16 |
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