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

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...

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Detalles Bibliográficos
Autores: Kaczor, Agnieszka A., Targowska-Duda, Katarzyna M., García Silva, Andrea, Kondej, Magda, Biała, Grażyna, Castro Pérez, María de los Ángeles
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad de Santiago de Compostela (USC)
Repositorio:Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela
Idioma:inglés
OAI Identifier:oai:minerva.usc.gal:10347/21687
Acceso en línea:http://hdl.handle.net/10347/21687
Access Level:acceso abierto
Descripción
Sumario: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.

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