Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes
Abstract Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute d...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-25478-7 |
| _version_ | 1811179157728526336 |
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| author | Damian Bartuzi Ewa Kędzierska Katarzyna M. Targowska-Duda Oliwia Koszła Tomasz M. Wróbel Simon Jademyr Tadeusz Karcz Katarzyna Szczepańska Piotr Stępnicki Olga Wronikowska-Denysiuk Grażyna Biała Jadwiga Handzlik Jesper L. Kristensen Antti Poso Agnieszka A. Kaczor |
| author_facet | Damian Bartuzi Ewa Kędzierska Katarzyna M. Targowska-Duda Oliwia Koszła Tomasz M. Wróbel Simon Jademyr Tadeusz Karcz Katarzyna Szczepańska Piotr Stępnicki Olga Wronikowska-Denysiuk Grażyna Biała Jadwiga Handzlik Jesper L. Kristensen Antti Poso Agnieszka A. Kaczor |
| author_sort | Damian Bartuzi |
| collection | DOAJ |
| description | Abstract Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands. |
| first_indexed | 2024-04-11T06:30:03Z |
| format | Article |
| id | doaj.art-e8d54c16692c4f768e6532bff908e43f |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T06:30:03Z |
| publishDate | 2022-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-e8d54c16692c4f768e6532bff908e43f2022-12-22T04:40:08ZengNature PortfolioScientific Reports2045-23222022-12-0112111410.1038/s41598-022-25478-7Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processesDamian Bartuzi0Ewa Kędzierska1Katarzyna M. Targowska-Duda2Oliwia Koszła3Tomasz M. Wróbel4Simon Jademyr5Tadeusz Karcz6Katarzyna Szczepańska7Piotr Stępnicki8Olga Wronikowska-Denysiuk9Grażyna Biała10Jadwiga Handzlik11Jesper L. Kristensen12Antti Poso13Agnieszka A. Kaczor14Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of LublinDepartment of Pharmacology and Pharmacodynamics, Faculty of Pharmacy, Medical University of LublinDepartment of Biopharmacy, Faculty of Pharmacy, Medical University of LublinDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of LublinDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of LublinDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical CollegeDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical CollegeDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of LublinIndependent Laboratory of Behavioral Studies, Chair of Biomedical Sciences, Faculty of Biomedicine, Medical University of LublinDepartment of Pharmacology and Pharmacodynamics, Faculty of Pharmacy, Medical University of LublinDepartment of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical CollegeDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of CopenhagenSchool of Pharmacy, University of Eastern FinlandDepartment of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Laboratory, Faculty of Pharmacy, Medical University of LublinAbstract Anxiety is a troublesome symptom for many patients, especially those suffering from schizophrenia. Its regulation involves serotonin receptors, targeted e.g. by antipsychotics or psychedelics such as LSD. 5-HT2A receptors are known for an extremely long LSD residence time, enabling minute doses to exert a long-lasting effect. In this work, we explore the changes in anxiety-like processes induced by the previously reported antipsychotic, D2AAK1. In vivo studies revealed that the effect of D2AAK1 on the anxiety is mediated through serotonin 5-HT1A and 5-HT2A receptors, and that it is time-dependent (anxiogenic after 30 min, anxiolytic after 60 min) and dose-dependent. The funnel metadynamics simulations suggest complicated ligand-5HT2AR interactions, involving an allosteric site located under the third extracellular loop, which is a possible explanation of the time-dependency. The binding of D2AAK1 at the allosteric site results in a broader opening of the extracellular receptor entry, possibly altering the binding kinetics of orthosteric ligands.https://doi.org/10.1038/s41598-022-25478-7 |
| spellingShingle | Damian Bartuzi Ewa Kędzierska Katarzyna M. Targowska-Duda Oliwia Koszła Tomasz M. Wróbel Simon Jademyr Tadeusz Karcz Katarzyna Szczepańska Piotr Stępnicki Olga Wronikowska-Denysiuk Grażyna Biała Jadwiga Handzlik Jesper L. Kristensen Antti Poso Agnieszka A. Kaczor Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes Scientific Reports |
| title | Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes |
| title_full | Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes |
| title_fullStr | Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes |
| title_full_unstemmed | Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes |
| title_short | Funnel metadynamics and behavioral studies reveal complex effect of D2AAK1 ligand on anxiety-like processes |
| title_sort | funnel metadynamics and behavioral studies reveal complex effect of d2aak1 ligand on anxiety like processes |
| url | https://doi.org/10.1038/s41598-022-25478-7 |
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