N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1Hbenzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic
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Título: | N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1Hbenzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic |
Autor/a: | Kaczor, Agnieszka A. Targowska Duda, Katarzyna M. García Silva, Andrea Kondej, Magda Biała, Grażyna Castro Pérez, María de los Ángeles |
Centro/Departamento: | Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica |
Palabras chave: | Antipsychotics | Behavioral Studies | Drug Design | In Vitro Studies | Molecular Modeling | Schizophrenia | |
Data: | 2020 |
Editor: | MDPI |
Cita bibliográfica: | Kaczor, A., Targowska-Duda, K., Silva, A., Kondej, M., Biała, G., & Castro, M. (2020). N-(2-Hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)propyl]piperidine-4-Carboxamide (D2AAK4), a Multi-Target Ligand of Aminergic GPCRs, as a Potential Antipsychotic. Biomolecules, 10(2), 349. https://doi.org/10.3390/biom10020349 |
Resumo: | N-(2-hydroxyphenyl)-1-[3-(2-oxo-2,3-dihydro-1H-benzimidazol -1-yl)propyl]piperidine-4-carboxamide (D2AAK4) is a multitarget ligand of aminergic G protein-coupled receptors (GPCRs) identified in structure-based virtual screening. Here we present detailed in vitro, in silico and in vivo investigations of this virtual hit. D2AAK4 has an atypical antipsychotic profile and low affinity to off-targets. It interacts with aminergic GPCRs, forming an electrostatic interaction between its protonatable nitrogen atom and the conserved Asp 3.32 of the receptors. At the dose of 100 mg/kg D2AAK4 decreases amphetamine-induced hyperactivity predictive of antipsychotic activity, improves memory consolidation in passive avoidance test and has anxiogenic properties in elevated plus maze test (EPM). Further optimization of the virtual hit D2AAK4 will be aimed to balance its multitarget profile and to obtain analogs with anxiolytic activity. |
Versión do editor: | https://doi.org/10.3390/biom10020349 |
URI: | http://hdl.handle.net/10347/21687 |
DOI: | 10.3390/biom10020349 |
E-ISSN: | 2218-273X |
Dereitos: | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) |
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