In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

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Background and Purpose:We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT 4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD).Experimental Approach: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-β peptides on neuronal survival and neurite formation determined in vitro.Key Results: In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation.In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.Conclusions and Implications: Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential diseasemodifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.