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

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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https://hal-cnrs.archives-ouvertes.fr/hal-03029988
Contributor : Philippe Marin Connect in order to contact the contributor
Submitted on : Sunday, November 29, 2020 - 5:45:58 PM
Last modification on : Monday, October 11, 2021 - 1:23:03 PM

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Vittorio Canale, Katarzyna Grychowska, Rafał Kurczab, Mateusz Ryng, Abdul 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, Elsevier, 2020, 208, pp.112765. ⟨10.1016/j.ejmech.2020.112765⟩. ⟨hal-03029988⟩

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