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 - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2023

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

Katarzyna Grychowska
Uriel López-Sánchez
  • Fonction : Auteur
Geoffrey Canet
  • Fonction : Auteur
Grzegorz Satała
Agnieszka Olejarz-Maciej
  • Fonction : Auteur
Joanna Gołębiowska
  • Fonction : Auteur
Rafał Kurczab
  • Fonction : Auteur
Wojciech Pietruś
  • Fonction : Auteur
Monika Kubacka
  • Fonction : Auteur
Christophe Moreau
Maria Walczak
Klaudia Blicharz-Futera
Andrzej Bojarski
Carine Becamel
Piotr Popik
Hugues Nury
Philippe Marin
Paweł Zajdel

Résumé

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.
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Origine : Publication financée par une institution
Licence : CC BY - Paternité

Dates et versions

hal-04235140 , version 1 (28-10-2023)

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Katarzyna Grychowska, Uriel López-Sánchez, Mathieu Vitalis, Geoffrey Canet, Grzegorz Satała, et al.. 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. Journal of Medicinal Chemistry, 2023, 66 (21), pp.14928-14947. ⟨10.1021/acs.jmedchem.3c01482⟩. ⟨hal-04235140⟩
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