Syracuse

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

Archive ouverte

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

Edité par CCSD ; Elsevier -

International audience. 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.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion