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

• Published in: European journal of medicinal chemistry 2024-12, Vol.280, p.116975, Article 116975
• Main Authors: Rochais, Christophe, Lecoutey, Cédric, Lalut, Julien, Davis, Audrey, Duval, Emilie, Gaven, Florence, Largillière, Stacy, Née, Gérald, Corvaisier, Sophie, Sopkova de Oliveira Santos, Jana, Since, Marc, Freret, Thomas, Legrand, Romain, Callizot, Noëlle, Claeysen, Sylvie, Boulouard, Michel, Dallemagne, Patrick
• Format: Article
• Language: English
• Subjects: 5-HT4; Acetylcholinesterase; Alzheimer's disease; Cognitive science; Human health and pathology; Life Sciences; Neuroscience; Pharmaceutical sciences; Pharmacology; Pleiotropic; Serotonin
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116975

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. [Display omitted] •Cholinesterase inhibition and 5-HT4R activation can be expressed by a same agent.•Flucopride is a novel Multi-Target-Directed Ligand.•Flucopride exemplifies the copride family of potential anti-Alzheimer agents.•Flucopride exerts both antiamnesiant and promnesiant properties in mice.