Azulene-based compounds for targeting orexin receptors

Teppo O Leino; Ainoleena Turku; Jari Yli-Kauhaluoma; Jyrki P Kukkonen; Henri Xhaard; Erik A A Wallén

doi:10.1016/j.ejmech.2018.07.040

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. Epub 2018 Jul 20.

Authors

Teppo O Leino¹, Ainoleena Turku², Jari Yli-Kauhaluoma³, Jyrki P Kukkonen⁴, Henri Xhaard³, Erik A A Wallén³

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.

MeSH terms

Azulenes / chemical synthesis
Azulenes / chemistry
Azulenes / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Orexin Receptors / agonists
Orexin Receptors / metabolism*
Structure-Activity Relationship

Substances

Azulenes
HCRTR1 protein, human
HCRTR2 protein, human
Orexin Receptors
azulene