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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.


ABSTRACT: 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 sAPP?. 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.

SUBMITTER: Hatat B 

PROVIDER: S-EPMC6611404 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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A Novel <i>in vivo</i> Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HT<sub>4</sub>R) Agonist and Serotonergic Subtype 6 Receptor (5-HT<sub>6</sub>R) Inverse Agonist Activities, With a Potential Interest Against Alzheimer's Disease.

Hatat Bérénice B   Yahiaoui Samir S   Lecoutey Cédric C   Davis Audrey A   Freret Thomas T   Boulouard Michel M   Claeysen Sylvie S   Rochais Christophe C   Dallemagne Patrick P  

Frontiers in aging neuroscience 20190619


This work describes the conception, synthesis, <i>in vitro</i> and <i>in vivo</i> 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 en  ...[more]

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