A Novel Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HTR) Agonist and Serotonergic Subtype 6 Receptor (5-HTR) Inverse Agonist Activities, With a Potential Interest Against Alzheimer's Disease.

This work describes the conception, synthesis, and biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT receptors, block 5-HT 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-HT and blockage of 5-HT receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT 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 ()], which displayed an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.