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. [Display omitted] •Virtual screening of synthetically accessible azulene-based compounds.•Synthesis and a biological evaluation of the compounds selected by the screening.•Azulene derivatives with low micromolar binding affinities to orexin receptors.•Identification of weak orexin receptor agonists.•Novel compounds potentiating the effects of orexin-A on OX1 receptor.