Azulene as a biphenyl mimetic in orexin/hypocretin receptor agonists
Leino, T. O., Turku, A., Urvas, L., Adhikari, K., Oksanen, J., Steynen, Y., Yli-Kauhaluoma, J., Xhaard, H., Kukkonen, J. P., & Wallén, E. A.A. (2023). Azulene as a biphenyl mimetic in orexin/hypocretin receptor agonists. Bioorganic and Medicinal Chemistry, 88-89, Article 117325. https://doi.org/10.1016/j.bmc.2023.117325
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Bioorganic and Medicinal ChemistryDate
2023Copyright
© 2023 The Author(s). Published by Elsevier Ltd.
Azulene is a rare ring structure in drugs, and we investigated whether it could be used as a biphenyl mimetic in known orexin receptor agonist Nag 26, which is binding to both orexin receptors OX1 and OX2 with preference towards OX2. The most potent azulene-based compound was identified as an OX1 orexin receptor agonist (pEC50 = 5.79 ± 0.07, maximum response = 81 ± 8% (s.e.m. of five independent experiments) of the maximum response to orexin-A in Ca2+ elevation assay). However, the azulene ring and the biphenyl scaffold are not identical in their spatial shape and electron distribution, and their derivatives may adopt different binding modes in the binding site.
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Postdoctoral Researcher, AoFAdditional information about funding
T.O.L. acknowledges the Doctoral Program in Drug Research of the University of Helsinki and the Academy of Finland (grant no. 330800); A.T. acknowledges the Finnish Cultural Foundation and the Orion Research Foundation; and J.P.K. acknowledges the Magnus Ehrnrooth Foundation, the Liv & Hälsa Foundation and Finska läkaresällskapet for financial support. Marja Peltola, Santeri Suokas and Maiju K. R ...
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