title: A new serotonin 5-HT6receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding.
abstract: Serotonin 5-HT6receptor 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-HT6receptor, 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-HT6receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4. In vitro pharmacological characterization of 5-HT6receptor antagonist 7 indicates high affinity and selectivity over a panel of receptors including 5-HT2Bsubtype 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.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: González-Vera
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Rocío A
authors.initials: RA
authors.lastname: Medina
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Martín-Fontecha
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Gonzalez
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: de la Fuente
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Henar
authors.initials: H
authors.lastname: Vázquez-Villa
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Cárceles
authors.affiliation: School of Pharmacy, University of East Anglia, NR4 7TJ Norwich, UK.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Botta
authors.affiliation: School of Pharmacy, University of East Anglia, NR4 7TJ Norwich, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McCormick
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.affiliation: Laboratori de Medicina Computacional, Unitat de Bioestadística, Facultat de Medicina, Universitat Autònoma de Barcelona, E-08193 Bellaterra, Spain.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Pardo
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, E-28040 Madrid, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D006219:Halogens / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040681:Structural Homology, Protein; D013647:Task Performance and Analysis
chemical_list: D001562:Benzimidazoles; D006219:Halogens; D008024:Ligands; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor