期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 121, 期 -, 页码 283-293出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.05.048
关键词
Alzheimer's disease; MTDL; 5-HT4 receptors agonists; 5-HT6 receptors antagonists
资金
- Conseil Regional de Basse Normandie, France (Dispositif de Soutien aux Projets de Recherche Emergents)
- European Union via the European Regional Development Fund (FEDER)
- French Foundation Plan Alzheimer
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 (sAPP alpha). 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 sub-micromolar 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. (C) 2016 Elsevier Masson SAS. All rights reserved.
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