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

González-Vera, Juan A., Medina, Rocío A., Martín-Fontecha, Mar, Gonzalez, Angel, de la Fuente, Tania, Vázquez-Villa, Henar, García-Cárceles, Javier, Botta, Joaquín, McCormick, Peter J., Benhamú, Bellinda, Pardo, Leonardo and López-Rodríguez, María L. (2017) A new serotonin 5-HT6 receptor antagonist with procognitive activity – Importance of a halogen bond interaction to stabilize the binding. Scientific Reports, 7. ISSN 2045-2322

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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.

Item Type: Article
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: Pure Connector
Date Deposited: 02 Feb 2017 03:49
Last Modified: 19 Sep 2019 00:14
URI: https://ueaeprints.uea.ac.uk/id/eprint/62278
DOI: 10.1038/srep41293

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