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Título:
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A new serotonin 5-HT 6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding
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Autores:
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González Vera, Juan Antonio ;
Medina Muñoz, Rocío Almudena ;
Martín Fontecha, María del Mar ;
Gonzalez Wong, Ángel ;
Fuente Mendizábal, Tania de la ;
Vázquez Villa, Henar ;
García Cárceles, Javier ;
Botta, Joaquín ;
McCormick, Peter J. ;
Benhamú Salama, Bellinda ;
Pardo Carrasco, Leonardo ;
López Rodríguez, María Luz
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Tipo de documento:
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texto impreso
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Editorial:
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Nature Publishing Group, 2017
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Dimensiones:
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application/pdf
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Nota general:
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cc_by
info:eu-repo/semantics/openAccess
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Idiomas:
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Palabras clave:
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Estado = Publicado
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Materia = Ciencias: Química: Bioquímica
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Materia = Ciencias Biomédicas: Medicina: Fisiología
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Materia = Ciencias Biomédicas: Medicina: Neurociencias
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Tipo = Artículo
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Resumen:
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Serotonin 5-HT 6 receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer's disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT 6 receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT 6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT 6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT 2B subtype and hERG channel, which suggests no major cardiac issues. Compound 7 exhibited in vivo procognitive activity (1 mg/kg, ip) in the novel object recognition task as a model of memory deficit.
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En línea:
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https://eprints.ucm.es/45642/1/Martin%20Fontecha_serotonin-ScientReports-Nature-2017.pdf
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