Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):E3825-30. doi: 10.1073/pnas.1410315111.

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer’s disease treatment

Cédric Lecouteya, Damien Hedoua, Thomas Freretb, Patrizia Giannonic,d,e, Florence Gavenc,d,e, Marc Sincea, Valentine Bouetb, Céline Ballandonnea, Sophie Corvaisiera,b, Aurélie Malzert Fréona, Serge Mignania, Thierry Cresteilf, Michel Boulouardb, Sylvie Claeysenc,d,e, Christophe Rochaisa,1, and Patrick Dallemagnea,1

 

aUniversité de Caen Basse-Normandie, Centre d’Etudes et de Recherche sur le Médicament de Normandie, F-14032 Caen, France; bUniversité de Caen Basse-Normandie, Groupe Mémoire et Plasticité comportementale, F-14032 Caen, France; cCentre National de la Recherche Scientifique, Unité Mixte de Recherche-5203, Institut de Génomique Fonctionnelle, F-34000 Montpellier, France; dInstitut National de la Santé et de la Recherche Médicale U661, F-34000 Montpellier, France; eUniversités de Montpellier 1 and 2, Unité Mixte de Recherche-5203, F-34000 Montpellier, France; and fInstitut de Chimie des Substances Naturelles, Centre National de la Recherche Scientifique Unité Propre de Recherche 2301, F-91198 Gif sur Yvette, France

 

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 multitargetdirected 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.

PMID: 25157130

 

Supplement

In this work we have discovered that RS67333, a reference 5-HT4R partial agonist, posseses a moderate activity towards acetylcholinesterase (AChE). Based on this results we have developed a series of novel Multitarget Directed Ligands (MTDL) towards two targets: AChE inhibition and 5-HT4 receptor activation. AChE inhibition is the action mechanism of donepezil, one of the current available drugs for Alzheimer’s Disease (AD). Activation of 5-HT4 receptors promotes the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and the release of the neuroprotective soluble APPalpha fragment. Single chemical compound able to act simultaneously towards the two targets could possibly exert a symptomatic but also a disease modifying effect in AD

Starting from this first hit we have conducted a pharmacomodulation strategy to develop a small library of MTDL possessing the expected activities. Among them, donecopride appears to be the most promising compound with potent in vitro activities but also nice drugability properties.1 More interestingly this compound could increase in vivo the memory performance of mice in the novel object recognition test.

More recently we have described the first Structure-Activity Relationships for this family as well as docking studies of donecopride with the two targets (Figure 1).2 In this paper we also demonstrate the ability of donecopride to reverse the memory deficit in vivo induced by scopolamine.WBF picture

 

Acknowledgements

This work was supported by funding from the Conseil Régional de Basse Normandie, France (Dispositif de Soutien aux Projets de Recherche Emergents), the French Agence Nationale de la Recherche (project MALAD ANR-12-JS007-0012-01) and The Ligue Européenne Contre la Maladie d’Alzheimer (LECMA, grant number #12721).

 

Contact

Pr Christophe Rochais and Pr Patrick Dallemagne, CERMN – EA4258 Boulevard Becquerel, 14032 Caen, France +33 231 566 813 patrick.dallemagne@unicaen.fr; christophe.rochais@unicaen.fr

 

References:

(1)      Lecoutey, C.; Hedou, D.; Freret, T.; Giannoni, P.; Gaven, F.; Since, M.; Bouet, V.; Ballandonne, C.; Corvaisier, S.; Malzert Fréon, A.; Mignani, S.; Cresteil, T.; Boulouard, M.; Claeysen, S.; Rochais, C.; Dallemagne, P. Design of Donecopride, a Dual Serotonin Subtype 4 Receptor Agonist/acetylcholinesterase Inhibitor with Potential Interest for Alzheimer’s Disease Treatment. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, E3825–E3830.

(2)      Rochais, C.; Lecoutey, C.; Gaven, F.; Giannoni, P.; Hamidouche, K.; Hedou, D.; Dubost, E.; Genest, D.; Yahiaoui, S.; Freret, T.; Bouet, V.; Dauphin, F.; Sopkova-de Oliveira Santos, J.; Ballandonne, C.; Corvaisier, S.; Malzert-Freon, A.; Legay, R.; Boulouard, M.; Claeysen, S.; Dallemagne, P. Novel Multi-Target 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. J. Med. Chem. 2015, 58, 3172–3187.

 

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