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 mu M 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. (C) 2018 Elsevier Masson SAS. All rights reserved.
Original languageEnglish
JournalEuropean Journal of Medicinal Chemistry
Volume157
Pages (from-to)88-100
Number of pages13
ISSN0223-5234
DOIs
Publication statusPublished - 5 Sep 2018
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • 116 Chemical sciences
  • Azulene
  • Orexin receptor
  • Potentiator
  • Agonist
  • Antagonist
  • Sleep-wake regulation
  • PROTEIN-COUPLED RECEPTORS
  • HAMSTER OVARY CELLS
  • SIGNAL-TRANSDUCTION
  • CA2+ INFLUX
  • OX1
  • DERIVATIVES
  • INHIBITORS
  • PEPTIDES
  • LIGANDS
  • KINASE

Cite this

@article{be64b9c4f27c4b99990288569234386b,
title = "Azulene-based compounds for targeting orexin receptors",
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 mu M 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. (C) 2018 Elsevier Masson SAS. All rights reserved.",
keywords = "317 Pharmacy, 116 Chemical sciences, Azulene, Orexin receptor, Potentiator, Agonist, Antagonist, Sleep-wake regulation, PROTEIN-COUPLED RECEPTORS, HAMSTER OVARY CELLS, SIGNAL-TRANSDUCTION, CA2+ INFLUX, OX1, DERIVATIVES, INHIBITORS, PEPTIDES, LIGANDS, KINASE",
author = "Leino, {Teppo O.} and Ainoleena Turku and Yli-Kauhaluoma, {Jari Tapani} and Kukkonen, {Jyrki P.} and Henri Xhaard and Wall{\'e}n, {Erik A. A.}",
year = "2018",
month = "9",
day = "5",
doi = "10.1016/j.ejmech.2018.07.040",
language = "English",
volume = "157",
pages = "88--100",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER",

}

TY - JOUR

T1 - Azulene-based compounds for targeting orexin receptors

AU - Leino, Teppo O.

AU - Turku, Ainoleena

AU - Yli-Kauhaluoma, Jari Tapani

AU - Kukkonen, Jyrki P.

AU - Xhaard, Henri

AU - Wallén, Erik A. A.

PY - 2018/9/5

Y1 - 2018/9/5

N2 - 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 mu M 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. (C) 2018 Elsevier Masson SAS. All rights reserved.

AB - 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 mu M 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. (C) 2018 Elsevier Masson SAS. All rights reserved.

KW - 317 Pharmacy

KW - 116 Chemical sciences

KW - Azulene

KW - Orexin receptor

KW - Potentiator

KW - Agonist

KW - Antagonist

KW - Sleep-wake regulation

KW - PROTEIN-COUPLED RECEPTORS

KW - HAMSTER OVARY CELLS

KW - SIGNAL-TRANSDUCTION

KW - CA2+ INFLUX

KW - OX1

KW - DERIVATIVES

KW - INHIBITORS

KW - PEPTIDES

KW - LIGANDS

KW - KINASE

U2 - 10.1016/j.ejmech.2018.07.040

DO - 10.1016/j.ejmech.2018.07.040

M3 - Article

VL - 157

SP - 88

EP - 100

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -