A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding

Juan A. González-Vera, Rocío A. Medina, Mar Martín-Fontecha, Angel Gonzalez, Tania de la Fuente, Henar Vázquez-Villa, Javier García-Cárceles, Joaquín Botta, Peter J. McCormick, Bellinda Benhamú, Leonardo Pardo, María L. López-Rodríguez

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Abstract

Serotonin 5-HT6 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-HT6 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-HT6 receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6 receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2B 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.
Original languageEnglish
Article number41293
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 24 Jan 2017

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