Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor Ligands
Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (<b>7a–i</b>) derivatives were synthesized. The chemical structures of the new compounds were confirmed by <sup>1</sup>H and <sup>13</sup>C NMR spectr...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/5/2329 |
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| author | Marek Król Grzegorz Ślifirski Jerzy Kleps Szymon Ulenberg Mariusz Belka Tomasz Bączek Agata Siwek Katarzyna Stachowicz Bernadeta Szewczyk Gabriel Nowak Beata Duszyńska Franciszek Herold |
| author_facet | Marek Król Grzegorz Ślifirski Jerzy Kleps Szymon Ulenberg Mariusz Belka Tomasz Bączek Agata Siwek Katarzyna Stachowicz Bernadeta Szewczyk Gabriel Nowak Beata Duszyńska Franciszek Herold |
| author_sort | Marek Król |
| collection | DOAJ |
| description | Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (<b>7a–i</b>) derivatives were synthesized. The chemical structures of the new compounds were confirmed by <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT<sub>1A</sub> receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT<sub>1A</sub> receptor of all derivatives in the series (<b>6a–i</b> and <b>7a–i</b>) and generally low binding affinities for the SERT protein, with the exception of compounds <b>6a</b> and <b>7g</b>. Extended affinity tests for the receptors D<sub>2</sub>, 5-HT<sub>2A</sub>, 5-HT<sub>6</sub> and 5-HT<sub>7</sub> were conducted with regard to selected compounds (<b>6a</b>, <b>7g</b>, <b>6d</b> and <b>7i</b>). All four compounds demonstrated very high affinities for the D<sub>2</sub> and 5-HT<sub>2A</sub> receptors. Compounds <b>6a</b> and <b>7g</b> also had high affinities for 5-HT<sub>7</sub>, while <b>6d</b> and <b>7i</b> held moderate affinities for this receptor. Compounds <b>6a</b> and <b>7g</b> were also tested in vivo to identify their functional activity profiles with regard to the 5-HT<sub>1A</sub> receptor, with <b>6a</b> demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for <b>6a</b> and <b>6d</b>. |
| first_indexed | 2024-03-09T00:30:51Z |
| format | Article |
| id | doaj.art-c4eac4054efd417aa89f45d49c6c6d82 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:30:51Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c4eac4054efd417aa89f45d49c6c6d822023-12-11T18:31:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01225232910.3390/ijms22052329Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor LigandsMarek Król0Grzegorz Ślifirski1Jerzy Kleps2Szymon Ulenberg3Mariusz Belka4Tomasz Bączek5Agata Siwek6Katarzyna Stachowicz7Bernadeta Szewczyk8Gabriel Nowak9Beata Duszyńska10Franciszek Herold11Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandDepartment of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandDepartment of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandDepartment of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, PolandDepartment of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, PolandDepartment of Pharmaceutical Chemistry, Medical University of Gdańsk, 107, J. Hallera Street, 80-416 Gdańsk, PolandDepartment of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9, Medyczna Street, 30-688 Kraków, PolandMaj Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, PolandMaj Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, PolandDepartment of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, 9, Medyczna Street, 30-688 Kraków, PolandMaj Institute of Pharmacology, Polish Academy of Sciences, 12, Smętna Street, 31-343 Kraków, PolandDepartment of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1, Banacha Street, 02-097 Warsaw, PolandTwo series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a–i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (<b>7a–i</b>) derivatives were synthesized. The chemical structures of the new compounds were confirmed by <sup>1</sup>H and <sup>13</sup>C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT<sub>1A</sub> receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT<sub>1A</sub> receptor of all derivatives in the series (<b>6a–i</b> and <b>7a–i</b>) and generally low binding affinities for the SERT protein, with the exception of compounds <b>6a</b> and <b>7g</b>. Extended affinity tests for the receptors D<sub>2</sub>, 5-HT<sub>2A</sub>, 5-HT<sub>6</sub> and 5-HT<sub>7</sub> were conducted with regard to selected compounds (<b>6a</b>, <b>7g</b>, <b>6d</b> and <b>7i</b>). All four compounds demonstrated very high affinities for the D<sub>2</sub> and 5-HT<sub>2A</sub> receptors. Compounds <b>6a</b> and <b>7g</b> also had high affinities for 5-HT<sub>7</sub>, while <b>6d</b> and <b>7i</b> held moderate affinities for this receptor. Compounds <b>6a</b> and <b>7g</b> were also tested in vivo to identify their functional activity profiles with regard to the 5-HT<sub>1A</sub> receptor, with <b>6a</b> demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for <b>6a</b> and <b>6d</b>.https://www.mdpi.com/1422-0067/22/5/2329antidepressantspyrido[1,2-<i>c</i>]pyrimidinesdual 5-HT<sub>1A</sub>/SERT activitydrug design |
| spellingShingle | Marek Król Grzegorz Ślifirski Jerzy Kleps Szymon Ulenberg Mariusz Belka Tomasz Bączek Agata Siwek Katarzyna Stachowicz Bernadeta Szewczyk Gabriel Nowak Beata Duszyńska Franciszek Herold Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor Ligands International Journal of Molecular Sciences antidepressants pyrido[1,2-<i>c</i>]pyrimidines dual 5-HT<sub>1A</sub>/SERT activity drug design |
| title | Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor Ligands |
| title_full | Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor Ligands |
| title_fullStr | Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor Ligands |
| title_full_unstemmed | Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor Ligands |
| title_short | Synthesis of Novel Pyrido[1,2-<i>c</i>]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT<sub>1A</sub> Receptor Ligands |
| title_sort | synthesis of novel pyrido 1 2 i c i pyrimidine derivatives with 6 fluoro 3 4 piperidynyl 1 2 benzisoxazole moiety as potential ssri and 5 ht sub 1a sub receptor ligands |
| topic | antidepressants pyrido[1,2-<i>c</i>]pyrimidines dual 5-HT<sub>1A</sub>/SERT activity drug design |
| url | https://www.mdpi.com/1422-0067/22/5/2329 |
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