González Vera, Juan AntonioMedina Muñoz, Rocío AlmudenaMartín-Fontecha Corrales, María Del MarGonzalez Wong, ÁngelFuente Mendizábal, Tania de laVázquez Villa, María Del HenarGarcía Cárceles, JavierBotta, JoaquínMcCormick, Peter J.Benhamú Salama, BellindaPardo Carrasco, LeonardoLópez Rodríguez, María Luz2023-06-172023-06-1720172045-232210.1038/srep41293https://hdl.handle.net/20.500.14352/18265received: 01 August 2016 accepted: 16 December 2016 Published: 24 January 2017Serotonin 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.engAtribución 3.0 Españahttps://creativecommons.org/licenses/by/3.0/es/journal articlehttp://dx.doi.org/10.1038/srep41293https://www.nature.com/articles/srep41293open access577.175.823616.894-053.9576.314Serotonin5-HT6 receptor antagonistDrug developmentStructure-based drug designCognition enhancementAlzheimer's diseaseMEmory deficiencyBioquímica (Química)FisiologíaNeurociencias (Medicina)2411 Fisiología Humana2490 Neurociencias