2. Academic Validation
  3. Azulene-based compounds for targeting orexin receptors

Azulene-based compounds for targeting orexin receptors

  • Eur J Med Chem. 2018 Sep 5;157:88-100. doi: 10.1016/j.ejmech.2018.07.040.
Teppo O Leino 1,  Ainoleena Turku 2,  Jari Yli-Kauhaluoma 3,  Jyrki P Kukkonen 4,  Henri Xhaard 3,  Erik A A Wallén 3
Affiliations

Affiliations

  • 1 Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014, University of Helsinki, Finland. Electronic address: teppo.leino@helsinki.fi.
  • 2 Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014, University of Helsinki, Finland; Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, FI-00014, University of Helsinki, Finland.
  • 3 Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FI-00014, University of Helsinki, Finland.
  • 4 Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, FI-00014, University of Helsinki, Finland; Department of Physiology, Faculty of Medicine, University of Helsinki, P.O. Box 63, FI-00014, University of Helsinki, Finland.
PMID: 30077889 DOI: 10.1016/j.ejmech.2018.07.040
Abstract

A library of 70 000 synthetically accessible azulene-based compounds was virtually screened at the OX2 receptor. Based on the results, a series of azulene derivatives was synthesized and the binding to and activation of both orexin receptor subtypes were assessed. Two most promising binders were determined to have inhibition constants in the 3-9 μM range and two other compounds showed weak OX2 receptor agonism. Furthermore, three compounds exhibited a concentration-dependent potentiation of the response to orexin-A at the OX1 but not the OX2 receptors. Altogether this data opens new approaches for further development of antagonists, agonists, and potentiators of orexin response based on the azulene scaffold.

Keywords

Agonist; Antagonist; Azulene; Orexin receptor; Potentiator; Sleep-wake regulation.

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