title: Synergistic effect of acetylcholinesterase inhibition (donepezil) and 5-HT(4) receptor activation (RS67333) on object recognition in mice.
abstract: Facing inefficiency of current treatments to cure Alzheimer disease (AD), a pharmacological approach is now emerging on the assumption that a single compound may be able to hit multiple targets, namely Multi-Target-Directed Ligands (MTDLs). Displaying numerous advantages, several MTDL for AD have been recently described but none associating an inhibition of AChE and an activation of 5-HT(4)R. The aim of this study was to validate the concept of a synergistic action of these two targets on episodic-like memory performances in mice. Among potent molecules, RS67333, a reference 5-HT(4)R agonist and donepezil (DNPZ), a reference acetylcholinesterase inhibitor, have been particularly chosen because of their close chemical structure. Administered separately, RS67333 (0.3 and 1mg/kg) and DNPZ (1mg/kg) improved recognition performances compared to saline treated animals but not with lower doses. Co-administration of subactive doses of RS67333 (0.1mg/kg) and DNPZ (0.3mg/kg) improved memory, moreover, this improvement is prevented if a 5-HT(4)R antagonist (GR125487, 10mg/kg) is also administered. Activation of 5-HT(4)R combined with inhibition of AChE with subactive doses of RS67333 and of DNPZ has synergistic effects on memory performances in mice. These molecules having close chemical structures, the synergistic effect of their combination affords new hope to chemist for the synthesis of MTDL.
authors.affiliation: Université de Caen Basse, Normandie, EA 4259 - Groupe Mémoire & Plasticité comportementale, F-14032 Caen, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Freret
authors.forename: Valentine
authors.initials: V
authors.lastname: Bouet
authors.forename: Anne
authors.initials: A
authors.lastname: Quiedeville
authors.forename: Gérald
authors.initials: G
authors.lastname: Nee
authors.forename: Patrick
authors.initials: P
authors.lastname: Dallemagne
authors.forename: Christophe
authors.initials: C
authors.lastname: Rochais
authors.forename: Michel
authors.initials: M
authors.lastname: Boulouard
mesh_terms: D000704:Analysis of Variance; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007189:Indans / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*; D021641:Recognition, Psychology / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000814:Aniline Compounds; D002800:Cholinesterase Inhibitors; D007189:Indans; D007211:Indoles; D010880:Piperidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; C107826:RS 67333; D000077265:Donepezil; C082871:GR 113808