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Eur J Med Chem ; 121: 283-293, 2016 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-27266998

RESUMEN

5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPα). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.


Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Diseño de Fármacos , Terapia Molecular Dirigida , Receptores de Serotonina 5-HT4/metabolismo , Receptores de Serotonina/metabolismo , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Animales , Técnicas de Química Sintética , Cobayas , Células HEK293 , Humanos , Ligandos , Masculino , Ratones , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Piperidinas/uso terapéutico , Agonistas del Receptor de Serotonina 5-HT4/síntesis química , Agonistas del Receptor de Serotonina 5-HT4/química , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico
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