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Nature Research, Scientific Reports, 1(7), 2017

DOI: 10.1038/srep41293

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

Journal article published in 2017 by Juan A. González-Vera, Rocío A. Medina, Mar Martín-Fontecha ORCID, Angel Gonzalez ORCID, Tania de la Fuente, Henar Vázquez-Villa ORCID, Javier García-Cárceles, Joaquín Botta, Peter J. McCormick, Bellinda Benhamú, Leonardo Pardo ORCID, María L. López-Rodríguez ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

AbstractSerotonin 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.