1. Academic Validation
  2. A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

A dual-acting 5-HT6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

  • Eur J Med Chem. 2020 Dec 15;208:112765. doi: 10.1016/j.ejmech.2020.112765.
Vittorio Canale 1 Katarzyna Grychowska 1 Rafał Kurczab 2 Mateusz Ryng 2 Abdul Raheem Keeri 1 Grzegorz Satała 2 Agnieszka Olejarz-Maciej 3 Paulina Koczurkiewicz 4 Marcin Drop 1 Klaudia Blicharz 1 Kamil Piska 4 Elżbieta Pękala 4 Paulina Janiszewska 5 Martyna Krawczyk 6 Maria Walczak 5 Severine Chaumont-Dubel 7 Andrzej J Bojarski 2 Philippe Marin 7 Piotr Popik 6 Paweł Zajdel 8
Affiliations

Affiliations

  • 1 Jagiellonian University Medical College, Department of Medicinal Chemistry, 9 Medyczna Str., 30-688, Kraków, Poland.
  • 2 Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, 12 Smętna Str., 31-324, Kraków, Poland.
  • 3 Jagiellonian University Medical College, Department of Technology and Biotechnology of Drugs, 9 Medyczna Str., 30-688, Kraków, Poland.
  • 4 Jagiellonian University Medical College, Department of Pharmaceutical Biochemistry, 9 Medyczna Str., 30-688, Kraków, Poland.
  • 5 Jagiellonian University Medical College, Department of Toxicology, 9 Medyczna Str., 30-688, Kraków, Poland.
  • 6 Maj Institute of Pharmacology, Polish Academy of Sciences, Department of New Drug Development, 12 Smętna Str., 31-324, Kraków, Poland.
  • 7 Institut de Génomique Fonctionelle, Université de Montpellier, CNRS INSERM, 34094, Montpellier, France.
  • 8 Jagiellonian University Medical College, Department of Medicinal Chemistry, 9 Medyczna Str., 30-688, Kraków, Poland. Electronic address: [email protected].
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 priviliged scaffolds of 5-HT6R 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, artificial membrane permeability, no hepatotoxicity, 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.

Keywords

5-HT(6)R antagonists; Alzheimer’s disease; Cognition; Constitutive activity; Glia; MAO-B inhibitors; Multi-target directed ligands; Neurodegenerative disorders.

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