Universidad Complutense de Madrid
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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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González Vera, Juan Antonio y Medina Muñoz, Rocío Almudena y Martín Fontecha, María del Mar y Gonzalez Wong, Ángel y Fuente Mendizábal, Tania de la y Vázquez Villa, Henar y García Cárceles, Javier y Botta, Joaquín y McCormick, Peter J. y Benhamú Salama, Bellinda y Pardo Carrasco, Leonardo y López Rodríguez, María Luz (2017) A new serotonin 5-HT 6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding. Scientific Reports, 7 (41293). ISSN 2045-2322

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URL Oficial: http://dx.doi.org/10.1038/srep41293




Resumen

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.


Tipo de documento:Artículo
Información Adicional:

received: 01 August 2016
accepted: 16 December 2016
Published: 24 January 2017

Palabras clave:Serotonin; 5-HT6 receptor antagonist; Drug development; Structure-based drug design; Cognition enhancement; Alzheimer's disease; MEmory deficiency
Materias:Ciencias > Química > Bioquímica
Ciencias Biomédicas > Medicina > Fisiología
Ciencias Biomédicas > Medicina > Neurociencias
Código ID:45642
Depositado:11 Dic 2017 13:41
Última Modificación:11 Dic 2017 16:12

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