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Superiority of the Triple-Acting 5‑HT6R/5-HT3R Antagonist and MAO‑B Reversible Inhibitor PZ-1922 over 5‑HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats

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Version 2 2023-10-17, 15:38
Version 1 2023-10-05, 18:13
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posted on 2023-10-17, 15:38 authored by Katarzyna Grychowska, Uriel López-Sánchez, Mathieu Vitalis, Geoffrey Canet, Grzegorz Satała, Agnieszka Olejarz-Maciej, Joanna Gołębiowska, Rafał Kurczab, Wojciech Pietruś, Monika Kubacka, Christophe Moreau, Maria Walczak, Klaudia Blicharz-Futera, Ophélie Bento, Xavier Bantreil, Gilles Subra, Andrzej J. Bojarski, Frédéric Lamaty, Carine Becamel, Charleine Zussy, Séverine Chaumont-Dubel, Piotr Popik, Hugues Nury, Philippe Marin, Laurent Givalois, Paweł Zajdel
The multifactorial origin and neurochemistry of Alzheimer’s disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT6R antagonism and interaction with 5-HT3R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT6R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922, but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD.

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