title: Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment.
abstract: RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France;
authors.forename: Cédric
authors.initials: C
authors.lastname: Lecoutey
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France;
authors.forename: Damien
authors.initials: D
authors.lastname: Hedou
authors.affiliation: Université de Caen Basse-Normandie, Groupe Mémoire et Plasticité comportementale, F-14032 Caen, France;
authors.forename: Thomas
authors.initials: T
authors.lastname: Freret
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Institut National de la Santé et de la Recherche Médicale U661, F-34000 Montpellier, France; Universités de Montpellier 1 and 2, Unité Mixte de Recherche-5203, F-34000 Montpellier, France; and.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannoni
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Institut National de la Santé et de la Recherche Médicale U661, F-34000 Montpellier, France; Universités de Montpellier 1 and 2, Unité Mixte de Recherche-5203, F-34000 Montpellier, France; and.
authors.forename: Florence
authors.initials: F
authors.lastname: Gaven
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France;
authors.forename: Marc
authors.initials: M
authors.lastname: Since
authors.affiliation: Université de Caen Basse-Normandie, Groupe Mémoire et Plasticité comportementale, F-14032 Caen, France;
authors.forename: Valentine
authors.initials: V
authors.lastname: Bouet
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France;
authors.forename: Céline
authors.initials: C
authors.lastname: Ballandonne
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France; Université de Caen Basse-Normandie, Groupe Mémoire et Plasticité comportementale, F-14032 Caen, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Corvaisier
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France;
authors.forename: Aurélie
authors.initials: A
authors.lastname: Malzert Fréon
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France;
authors.forename: Serge
authors.initials: S
authors.lastname: Mignani
authors.affiliation: Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique Unité Propre de Recherche 2301, F-91198 Gif sur Yvette, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.affiliation: Université de Caen Basse-Normandie, Groupe Mémoire et Plasticité comportementale, F-14032 Caen, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Boulouard
authors.affiliation: Centre National de la Recherche Scientifique, Unité Mixte de Recherche-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; Institut National de la Santé et de la Recherche Médicale U661, F-34000 Montpellier, France; Universités de Montpellier 1 and 2, Unité Mixte de Recherche-5203, F-34000 Montpellier, France; and.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Claeysen
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France; christophe.rochais@unicaen.fr patrick.dallemagne@unicaen.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rochais
authors.affiliation: Université de Caen Basse-Normandie, Centre d'Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France; christophe.rochais@unicaen.fr patrick.dallemagne@unicaen.fr.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0002-4845-615X
authors.initials: P
authors.lastname: Dallemagne
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D051379:Mice; D010539:Permeability / Q000187:drug effects; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism / Q000627:therapeutic use; D020112:Rhodamine 123 / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012995:Solubility; D013647:Task Performance and Analysis
chemical_list: D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D002800:Cholinesterase Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D010880:Piperidines; D058828:Serotonin 5-HT4 Receptor Agonists; C000596879:donecopride; D044422:Receptors, Serotonin, 5-HT4; C107826:RS 67333; D020112:Rhodamine 123; D016572:Cyclosporine