Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives
In this study, a series of compounds derived from 4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1<i>H</i>-isoindole-1,3(...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/17/3868 |
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| author | Anna Czopek Anna Partyka Adam Bucki Maciej Pawłowski Marcin Kołaczkowski Agata Siwek Monika Głuch-Lutwin Paulina Koczurkiewicz Elżbieta Pękala Anna Jaromin Bożena Tyliszczak Anna Wesołowska Agnieszka Zagórska |
| author_facet | Anna Czopek Anna Partyka Adam Bucki Maciej Pawłowski Marcin Kołaczkowski Agata Siwek Monika Głuch-Lutwin Paulina Koczurkiewicz Elżbieta Pękala Anna Jaromin Bożena Tyliszczak Anna Wesołowska Agnieszka Zagórska |
| author_sort | Anna Czopek |
| collection | DOAJ |
| description | In this study, a series of compounds derived from 4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT<sub>1A</sub> and 5-HT<sub>7</sub> receptor affinities. Based on in vitro studies, the most potent compound, <b>18</b> (2-[4-(1<i>H</i>-benzimidazol-2-yl)butyl]-4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound <b>18</b> in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound <b>18</b> in a behavioral model of schizophrenia were also investigated. |
| first_indexed | 2024-03-10T16:50:57Z |
| format | Article |
| id | doaj.art-9d24b05e3f484edca4bfc643c64596ec |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T16:50:57Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-9d24b05e3f484edca4bfc643c64596ec2023-11-20T11:19:31ZengMDPI AGMolecules1420-30492020-08-012517386810.3390/molecules25173868Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione DerivativesAnna Czopek0Anna Partyka1Adam Bucki2Maciej Pawłowski3Marcin Kołaczkowski4Agata Siwek5Monika Głuch-Lutwin6Paulina Koczurkiewicz7Elżbieta Pękala8Anna Jaromin9Bożena Tyliszczak10Anna Wesołowska11Agnieszka Zagórska12Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacobiology, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmacobiology, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmaceutical Biochemistry, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Pharmaceutical Biochemistry, Jagiellonian University Collegium Medicum, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Lipids and Liposomes, Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, 50-383 Wroclaw, PolandFaculty of Materials Engineering and Physics, Cracow University of Technology, Institute of Materials Science, 24 Warszawska Street, 31-155 Krakow, PolandDepartment of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandDepartment of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, PolandIn this study, a series of compounds derived from 4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione, potential ligands of phosphodiesterase 10A and serotonin receptors, were investigated as potential antipsychotics. A library of 4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione derivatives with various amine moieties was synthesized and examined for their phosphodiesterase 10A (PDE10A)-inhibiting properties and their 5-HT<sub>1A</sub> and 5-HT<sub>7</sub> receptor affinities. Based on in vitro studies, the most potent compound, <b>18</b> (2-[4-(1<i>H</i>-benzimidazol-2-yl)butyl]-4-methoxy-1<i>H</i>-isoindole-1,3(2<i>H</i>)-dione), was selected and its safety in vitro was evaluated. In order to explain the binding mode of compound <b>18</b> in the active site of the PDE10A enzyme and describe the molecular interactions responsible for its inhibition, computer-aided docking studies were performed. The potential antipsychotic properties of compound <b>18</b> in a behavioral model of schizophrenia were also investigated.https://www.mdpi.com/1420-3049/25/17/3868benzimidazole derivativesphosphodiesterase 10Aschizophreniaantipsychotic activity |
| spellingShingle | Anna Czopek Anna Partyka Adam Bucki Maciej Pawłowski Marcin Kołaczkowski Agata Siwek Monika Głuch-Lutwin Paulina Koczurkiewicz Elżbieta Pękala Anna Jaromin Bożena Tyliszczak Anna Wesołowska Agnieszka Zagórska Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives Molecules benzimidazole derivatives phosphodiesterase 10A schizophrenia antipsychotic activity |
| title | Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives |
| title_full | Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives |
| title_fullStr | Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives |
| title_full_unstemmed | Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives |
| title_short | Impact of N-Alkylamino Substituents on Serotonin Receptor (5-HTR) Affinity and Phosphodiesterase 10A (PDE10A) Inhibition of Isoindole-1,3-dione Derivatives |
| title_sort | impact of n alkylamino substituents on serotonin receptor 5 htr affinity and phosphodiesterase 10a pde10a inhibition of isoindole 1 3 dione derivatives |
| topic | benzimidazole derivatives phosphodiesterase 10A schizophrenia antipsychotic activity |
| url | https://www.mdpi.com/1420-3049/25/17/3868 |
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