Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT 4 R) partial agonist and 5-HT 6 R antagonist activities, as potential treatment of Alzheimer’s disease - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2016

Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT 4 R) partial agonist and 5-HT 6 R antagonist activities, as potential treatment of Alzheimer’s disease

Résumé

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
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Dates et versions

hal-02043759 , version 1 (21-02-2019)

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Samir Yahiaoui, Katia Hamidouche, Céline Ballandonne, Audrey Davis, Jana Sopkova-de Oliveira Santos, et al.. Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT 4 R) partial agonist and 5-HT 6 R antagonist activities, as potential treatment of Alzheimer’s disease. European Journal of Medicinal Chemistry, 2016, 121, pp.283-293. ⟨10.1016/j.ejmech.2016.05.048⟩. ⟨hal-02043759⟩
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