Novel Multitarget-Directed Ligands (MTDLs) with Acetylcholinesterase (AChE) Inhibitory and Serotonergic Subtype 4 Receptor (5-HT 4 R) Agonist Activities As Potential Agents against Alzheimer’s Disease: The Design of Donecopride

Cédric Lecoutey (1) , Cédric Lecoutey (1) , Florence Gaven (2) , Patrizia Giannoni (2) , Katia Hamidouche (3) , Damien Hedou (1) , Emmanuelle Dubost (1) , David Genest (1) , Samir Yahiaoui (1) , Thomas Freret (3) , Valentine Bouet (3) , François Dauphin (3) , Jana Sopkova-de Oliveira Santos (1) , Céline Ballandonne (1) , Sophie Corvaisier (1) , Aurélie Malzert-Fréon (1) , Rémi Legay (1) , Michel Boulouard (3) , Sylvie Claeysen (2) , Patrick Dallemagne (1)

1 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
2 IGF - Institut de Génomique Fonctionnelle
3 GMPc - Groupe Mémoire et Plasticité comportementale

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer’s disease.

Mots clés: Alzheimer's Disease; Acetylcholinesterase; 5-HT4 Receptors; Donecopride; MTDL

Domaines: Chimie thérapeutique

Cédric Lecoutey, Cédric Lecoutey, Florence Gaven, Patrizia Giannoni, Katia Hamidouche, et al.. Novel Multitarget-Directed Ligands (MTDLs) with Acetylcholinesterase (AChE) Inhibitory and Serotonergic Subtype 4 Receptor (5-HT 4 R) Agonist Activities As Potential Agents against Alzheimer’s Disease: The Design of Donecopride. Journal of Medicinal Chemistry, 2015, 58 (7), pp.3172-3187. ⟨10.1021/acs.jmedchem.5b00115⟩. ⟨hal-02043873⟩