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

Q1 · MEDICINE

Article

Author: Givalois, Laurent ; Gołębiowska, Joanna ; Kubacka, Monika ; Vitalis, Mathieu ; Bantreil, Xavier ; Moreau, Christophe ; Blicharz-Futera, Klaudia ; Satała, Grzegorz ; Subra, Gilles ; Walczak, Maria ; Pietruś, Wojciech ; Canet, Geoffrey ; Kurczab, Rafał ; Chaumont-Dubel, Séverine ; Grychowska, Katarzyna ; Bojarski, Andrzej J ; Nury, Hugues ; Lamaty, Frédéric ; Zajdel, Paweł ; Becamel, Carine ; Marin, Philippe ; Popik, Piotr ; 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.

01 Dec 2020·European Journal of Medicinal ChemistryQ1 · MEDICINE

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

Q1 · MEDICINE

Article

Author: Janiszewska, Paulina ; Koczurkiewicz, Paulina ; Kurczab, Rafał ; Canale, Vittorio ; Blicharz, Klaudia ; Grychowska, Katarzyna ; Popik, Piotr ; Satała, Grzegorz ; Marin, Philippe ; Krawczyk, Martyna ; Piska, Kamil ; Ryng, Mateusz ; Chaumont-Dubel, Severine ; Keeri, Abdul Raheem ; Bojarski, Andrzej J ; Walczak, Maria ; Drop, Marcin ; Olejarz-Maciej, Agnieszka ; Pękala, Elżbieta ; Zajdel, Paweł

The complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT₆ receptor (5-HT₆R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking priviliged scaffolds of 5-HT₆R with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT₆R at G_s signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay, artificial membrane permeability, no hepatotoxicity, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT₆R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies.

01 Mar 2014·Journal of Biological ChemistryQ2 · BIOLOGY

Serotonin Receptor 6 Mediates Defective Brain Development in Monoamine Oxidase A-deficient Mouse Embryos

Q2 · BIOLOGY

Article

Author: Gene Chi Wai Man ; Astrid Borchert ; Hartmut Kühn ; Ching Yan Chu ; E. Ellen Billett ; Chi Chiu Wang ; Christoph Ufer ; Aslihan Ugun-Klusek

Monoamine oxidases A and B (MAO-A and MAO-B) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines. In the adult central nervous system, MAOs have important functions for neurotransmitter homeostasis. Expression of MAO isoforms has been detected in the developing embryo. However, suppression of MAO-B does not induce developmental alterations. In contrast, targeted inhibition and knockdown of MAO-A expression (E7.5-E10.5) caused structural abnormalities in the brain. Here we explored the molecular mechanisms underlying defective brain development induced by MAO-A knockdown during in vitro embryogenesis. The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures. Moreover, dysfunctional MAO-A expression led to elevated levels of embryonic serotonin (5-hydroxytryptamine (5-HT)), and we found that knockdown of serotonin receptor-6 (5-Htr6) expression or pharmacologic inhibition of 5-Htr6 activity rescued the MAO-A knockdown phenotype and restored apoptotic activity in the developing brain. Our data suggest that excessive 5-Htr6 activation reduces activation of caspase-3 and -9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl-2 and Bcl-XL. Moreover, we found that elevated 5-HT levels in MAO-A knockdown embryos coincided with an enhanced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and a reduction of proliferating cell numbers. In summary, our findings suggest that excessive 5-HT in MAO-A-deficient mouse embryos triggers cellular signaling cascades via 5-Htr6, which suppresses developmental apoptosis in the brain and thus induces developmental retardations.

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