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  3. Synthesis, in vitro and in vivo biological evaluation of novel dual compounds targeting both acetylcholinesterase and serotonergic 5-HT4 receptors with potential interest in the treatment of Alzheimer's disease

Synthesis, in vitro and in vivo biological evaluation of novel dual compounds targeting both acetylcholinesterase and serotonergic 5-HT4 receptors with potential interest in the treatment of Alzheimer's disease

  • Eur J Med Chem. 2024 Dec 15:280:116975. doi: 10.1016/j.ejmech.2024.116975.
Christophe Rochais 1,  Cédric Lecoutey 2,  Julien Lalut 2,  Audrey Davis 2,  Emilie Duval 2,  Florence Gaven 3,  Stacy Largillière 4,  Gérald Née 4,  Sophie Corvaisier 2,  Jana Sopkova de Oliveira Santos 2,  Marc Since 5,  Thomas Freret 4,  Romain Legrand 6,  Noëlle Callizot 7,  Sylvie Claeysen 3,  Michel Boulouard 4,  Patrick Dallemagne 8
Affiliations

Affiliations

  • 1 Université de Caen Normandie, Normandie Univ., Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), 14000 Caen, France. Electronic address: christophe.rochais@unicaen.fr.
  • 2 Université de Caen Normandie, Normandie Univ., Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), 14000 Caen, France.
  • 3 IGF, Univ. Montpellier, CNRS, INSERM, F-34094, Montpellier, France.
  • 4 Université de Caen Normandie, Normandie Univ., Mobilités: Vieillissement, Pathologie, Santé (COMETE), INSERM UMR-S 1075, 14000, Caen, France.
  • 5 Université de Caen Normandie, Normandie Univ., Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), 14000 Caen, France; PRISMM Platform, PLATON Service Unit, Caen, Université de Caen Normandie, France.
  • 6 RONOMA Pharma, 31 Rue Léon Delille, F-76800, Saint Etienne du Rouvray, France.
  • 7 Neuro-Sys, 410 Chemin départemental 60, F-13120, Gardanne, France.
  • 8 Université de Caen Normandie, Normandie Univ., Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), 14000 Caen, France. Electronic address: patrick.dallemagne@unicaen.fr.
PMID: 39454222 DOI: 10.1016/j.ejmech.2024.116975
Abstract

In this work, we exemplified the "copride" family of drug candidates able to both inhibit acetylcholinesterase and to activate 5-HT4 receptors, with anti-amnesiant and promnesiant activities in mice. Twenty-one analogs of donecopride, the first-in class representative of the series, were synthesized exploring the influence on the biological activities of the substituents (methoxy, amine and chlorine) carried by its phenyl ring. This work was the support of an intensive structure-activity relationship study and allowed to obtain some interesting derivatives of donecopride. In this respect, the replacement of the methoxy group of the latter with a deuterated one led to deudonecopride. On the other hand, the replacement of the chlorine atom of donecopride by various halogen atoms was of particular interest, among which fluorine led to a potent analog, we called flucopride. The latter exhibited promising in vitro activities associated to excellent drugability parameters. Flucopride was consequently involved in in vivo studies such as a scopolamine-induced deficit model of working memory and in a novel object recognition test. Through these evaluations, flucopride demonstrated both its antiamnesiant and promnesiant capacities, which could make it a potential preclinical drug candidate for the treatment of Alzheimer's disease.

Keywords

5-HT(4); Acetylcholinesterase; Alzheimer's disease; Pleiotropic; Serotonin.

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