AUTHOR=Hatat Bérénice , Yahiaoui Samir , Lecoutey Cédric , Davis Audrey , Freret Thomas , Boulouard Michel , Claeysen Sylvie , Rochais Christophe , Dallemagne Patrick 

TITLE=A Novel in vivo Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HT4R) Agonist and Serotonergic Subtype 6 Receptor (5-HT6R) Inverse Agonist Activities, With a Potential Interest Against Alzheimer’s Disease

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=11

YEAR=2019

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2019.00148

DOI=10.3389/fnagi.2019.00148

ISSN=1663-4365

ABSTRACT=<p>This work describes the conception, synthesis, <italic>in vitro</italic> and <italic>in vivo</italic> biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT<sub>4</sub> receptors, block 5-HT<sub>6</sub> 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<sub>4</sub> and blockage of 5-HT<sub>6</sub> receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT<sub>4</sub> 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 (<bold>10</bold>)], which displayed <italic>in vivo</italic> an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.</p>