1区 · 医学
Article
作者: Givalois, Laurent ; Gołębiowska, Joanna ; Kubacka, Monika ; Vitalis, Mathieu ; Bantreil, Xavier ; Moreau, Christophe ; Blicharz-Futera, Klaudia ; Satała, Grzegorz ; Subra, Gilles ; Walczak, Maria ; Pietruś, Wojciech ; Zajdel, Paweł ; Bojarski, Andrzej J ; Kurczab, Rafał ; Grychowska, Katarzyna ; Chaumont-Dubel, Séverine ; Nury, Hugues ; Lamaty, Frédéric ; Canet, Geoffrey ; Becamel, Carine ; Popik, Piotr ; Marin, Philippe ; Olejarz-Maciej, Agnieszka ; Zussy, Charleine ; López-Sánchez, Uriel ; Bento, Ophélie
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.
