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
  • 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].
PMID: 32949963 DOI: 10.1016/j.ejmech.2020.112765
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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