Superiority of the Triple-Acting 5-HT(6)R/5-HT(3)R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT(6)R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats

[Image: see text] 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.