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

• Published in: Journal of medicinal chemistry 2023-11, Vol.66 (21), p.14928-14947
• Main Authors: Grychowska, Katarzyna, López-Sánchez, Uriel, Vitalis, Mathieu, Canet, Geoffrey, Satała, Grzegorz, Olejarz-Maciej, Agnieszka, Gołębiowska, Joanna, Kurczab, Rafał, Pietruś, Wojciech, Kubacka, Monika, Moreau, Christophe, Walczak, Maria, Blicharz-Futera, Klaudia, Bento, Ophélie, Bantreil, Xavier, Subra, Gilles, Bojarski, Andrzej J., Lamaty, Frédéric, Becamel, Carine, Zussy, Charleine, Chaumont-Dubel, Séverine, Popik, Piotr, Nury, Hugues, Marin, Philippe, Givalois, Laurent, Zajdel, Paweł
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01482

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.