Superiority of the Triple-Acting 5-HT<sub>6</sub>R/5-HT<sub>3</sub>R Antagonist and MAO-B Reversible Inhibitor <b>PZ-1922</b> over 5-HT<sub>6</sub>R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats
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 Bécamel, Charleine Zussy, Séverine Chaumont‐Dubel, Piotr Popik, Hugues Nury, Philippe Marin, Laurent Givalois, Paweł Zajdel
Abstract
High Resolution Image Download MS PowerPoint Slide 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-HT 6 R antagonism and interaction with 5-HT 3 R 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-HT 6 R 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-HT 6 R/5-HT 3 R/MAO-B in AD.