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

  • J Med Chem. 2023 Oct 5. doi: 10.1021/acs.jmedchem.3c01482.
Katarzyna Grychowska  1 ,  Uriel López-Sánchez  2 ,  Mathieu Vitalis  3 ,  Geoffrey Canet  4 ,  Grzegorz Satała  5 ,  Agnieszka Olejarz-Maciej  1 ,  Joanna Gołębiowska  5 ,  Rafał Kurczab  5 ,  Wojciech Pietruś  5 ,  Monika Kubacka  1 ,  Christophe Moreau  2 ,  Maria Walczak  1 ,  Klaudia Blicharz-Futera  1 ,  Ophélie Bento  6  7 ,  Xavier Bantreil  6 ,  Gilles Subra  6 ,  Andrzej J Bojarski  5 ,  Frédéric Lamaty  6 ,  Carine Becamel  7 ,  Charleine Zussy  3 ,  Séverine Chaumont-Dubel  7 ,  Piotr Popik  5 ,  Hugues Nury  2 ,  Philippe Marin  7 ,  Laurent Givalois  3  4  8 ,  Paweł Zajdel  1
Affiliations
  • 1. Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688 Kraków, Poland.
  • 2. Univ. Grenoble Alpes, CNRS, CEA, IBS, F-38000 Grenoble, France.
  • 3. Molecular Mechanisms in Neurodegenerative Dementia (MMDN) Laboratory, University of Montpellier, EPHE-PSL, INSERM U1198, 34-095 Montpellier, France.
  • 4. Faculty of Medicine, Laval University, CR-CHUQ, G1 V 4G2 Québec City (QC), Canada.
  • 5. Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-324 Kraków, Poland.
  • 6. IBMM, Université de Montpellier, CNRS, ENSCM, 34-293 Montpellier, France.
  • 7. Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34-094 Montpellier, France.
  • 8. CNRS, 75-016 Paris, France.
PMID: 37797083 DOI: 10.1021/acs.jmedchem.3c01482
Abstract

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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