Azulene-based compounds for targeting orexin receptors

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.