A dual-acting 5-HT 6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties - Archive ouverte HAL Access content directly
Journal Articles European Journal of Medicinal Chemistry Year : 2020

A dual-acting 5-HT 6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

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

Abstract

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 5-HT6R scaffolds 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 Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay and artificial membrane permeability, 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.
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hal-03029988 , version 1 (29-11-2020)

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Vittorio Canale, Katarzyna Grychowska, Rafał Kurczab, Mateusz Ryng, Abdul Raheem Keeri, et al.. A dual-acting 5-HT 6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties. European Journal of Medicinal Chemistry, 2020, 208, pp.112765. ⟨10.1016/j.ejmech.2020.112765⟩. ⟨hal-03029988⟩
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