%0 Journal Article
%A González Vera, Juan Antonio
%A Medina Muñoz, Rocío Almudena
%A Martín-Fontecha Corrales, María Del Mar
%A Gonzalez Wong, Ángel
%A Fuente Mendizábal, Tania de la
%A Vázquez Villa, María Del Henar
%A García Cárceles, Javier
%A Botta, Joaquín
%A McCormick, Peter J.
%A Benhamú Salama, Bellinda
%A Pardo Carrasco, Leonardo
%A López Rodríguez, María Luz
%T A new serotonin 5-HT 6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding
%D 2017
%@ 2045-2322
%U https://hdl.handle.net/20.500.14352/18265
%X 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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