title: Novel multitarget-directed ligands (MTDLs) with acetylcholinesterase (AChE) inhibitory and serotonergic subtype 4 receptor (5-HT4R) agonist activities as potential agents against Alzheimer's disease: the design of donecopride.
abstract: 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.
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Christophe
authors: C
authors: Rochais
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Cédric
authors: C
authors: Lecoutey
authors: ‡CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.|§Inserm, U1191, F-34000 Montpellier, France.|∥Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors: Florence
authors: F
authors: Gaven
authors: ‡CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.|§Inserm, U1191, F-34000 Montpellier, France.|∥Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors: Patrizia
authors: P
authors: Giannoni
authors: ⊥UNICAEN, GMPc5 (Groupe Mémoire et Plasticité comportementale), F-14032 Caen, France.
authors: Katia
authors: K
authors: Hamidouche
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Damien
authors: D
authors: Hedou
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Emmanuelle
authors: E
authors: Dubost
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: David
authors: D
authors: Genest
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Samir
authors: S
authors: Yahiaoui
authors: ⊥UNICAEN, GMPc5 (Groupe Mémoire et Plasticité comportementale), F-14032 Caen, France.
authors: Thomas
authors: T
authors: Freret
authors: ⊥UNICAEN, GMPc5 (Groupe Mémoire et Plasticité comportementale), F-14032 Caen, France.
authors: Valentine
authors: V
authors: Bouet
authors: ⊥UNICAEN, GMPc5 (Groupe Mémoire et Plasticité comportementale), F-14032 Caen, France.
authors: François
authors: F
authors: Dauphin
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Jana
authors: J
authors: Sopkova de Oliveira Santos
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Céline
authors: C
authors: Ballandonne
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.|⊥UNICAEN, GMPc5 (Groupe Mémoire et Plasticité comportementale), F-14032 Caen, France.
authors: Sophie
authors: S
authors: Corvaisier
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Aurélie
authors: A
authors: Malzert-Fréon
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Remi
authors: R
authors: Legay
authors: ⊥UNICAEN, GMPc5 (Groupe Mémoire et Plasticité comportementale), F-14032 Caen, France.
authors: Michel
authors: M
authors: Boulouard
authors: ‡CNRS, UMR-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France.|§Inserm, U1191, F-34000 Montpellier, France.|∥Université de Montpellier, UMR-5203, F-34000 Montpellier, France.
authors: Sylvie
authors: S
authors: Claeysen
authors: †UNICAEN, CERMN (Centre d'Etudes et de Recherche sur le Médicament de Normandie), F-14032 Caen, France.
authors: Patrick
authors: P
authors: Dallemagne
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D000814:Aniline Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D058990:Molecular Targeted Therapy; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023382:Toxicity Tests, Acute
chemical_list: D000814:Aniline Compounds; D002800:Cholinesterase Inhibitors; D008024:Ligands; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; C000596879:donecopride; D044422:Receptors, Serotonin, 5-HT4