A new serotonin 5-HT 6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding

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 def...

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Detalles Bibliográficos
Autores: González Vera, Juan Antonio, Medina Muñoz, Rocío Almudena, Martín-Fontecha Corrales, María Del Mar, Gonzalez Wong, Ángel, Fuente Mendizábal, Tania de la, Vázquez Villa, María Del Henar, García Cárceles, Javier, Botta, Joaquín, McCormick, Peter J., Benhamú Salama, Bellinda, Pardo Carrasco, Leonardo, López Rodríguez, María Luz
Tipo de recurso: artículo
Fecha de publicación:2017
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/18265
Acceso en línea:https://hdl.handle.net/20.500.14352/18265
Access Level:acceso abierto
Palabra clave:577.175.823
616.894-053.9
576.314
Serotonin
5-HT6 receptor antagonist
Drug development
Structure-based drug design
Cognition enhancement
Alzheimer's disease
MEmory deficiency
Bioquímica (Química)
Fisiología
Neurociencias (Medicina)
2411 Fisiología Humana
2490 Neurociencias
Descripción
Sumario: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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