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            <funder>This work was supported by funding from the Fondation Vaincre Alzheimer (#FR-15072) and the Fondation Plan Alzheimer (AAP2015 Project TRIAD 016). The authors gratefully acknowledge the Conseil Régional de Normandie, as well as the European Community (FEDER) for theircontribution to the CERMN’s analytical platform. European COST action CA15135 (Multi-Target Paradigm for Innovative Ligand Identification in the Drug Discovery Process, MuTaLig) supports this article.</funder>
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              <p>This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer's disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan-1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.</p>
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