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A new serotonin 5-HT 6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding

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González Vera, Juan Antonio and Medina Muñoz, Rocío Almudena and Martín Fontecha, María del Mar and Gonzalez Wong, Ángel and Fuente Mendizábal, Tania de la and Vázquez Villa, Henar and García Cárceles, Javier and Botta, Joaquín and McCormick, Peter J. and Benhamú Salama, Bellinda and Pardo Carrasco, Leonardo and López Rodríguez, María Luz (2017) A new serotonin 5-HT 6 receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding. Scientific Reports, 7 (41293). ISSN 2045-2322

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Official URL: http://dx.doi.org/10.1038/srep41293




Abstract

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.


Item Type:Article
Additional Information:

received: 01 August 2016
accepted: 16 December 2016
Published: 24 January 2017

Uncontrolled Keywords:Serotonin; 5-HT6 receptor antagonist; Drug development; Structure-based drug design; Cognition enhancement; Alzheimer's disease; MEmory deficiency
Subjects:Sciences > Chemistry > Biochemistry
Medical sciences > Medicine > Physiology
Medical sciences > Medicine > Neurosciences
ID Code:45642
Deposited On:11 Dec 2017 13:41
Last Modified:11 Dec 2017 16:12

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