Abstract

We previously demonstrated the potential of di- or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the orexin receptors. In this study we investigated 27 1-benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX1 and two weak dual orexin receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure-activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen-bond acceptors (1-position, benzoyl; 6-position, carboxyl/ester) within 7-8 angstrom of each other; a third acceptor at the 3-position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the orexin receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.
Original languageEnglish
JournalChemMedChem : chemistry enabling drug discovery.
Volume14
Issue number9
Pages (from-to)965-981
Number of pages17
ISSN1860-7179
DOIs
Publication statusPublished - 6 May 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 317 Pharmacy
  • 1-benzoylazulenes
  • biological activity
  • drug discovery
  • medicinal chemistry
  • orexin receptors
  • SIGNAL-TRANSDUCTION
  • CA2+ INFLUX
  • AZULENE
  • DERIVATIVES
  • NONPEPTIDE
  • PEPTIDE
  • BINDING
  • DESIGN
  • KINASE

Cite this

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title = "Structure-activity relationships of 1-benzoylazulenes at the OX1 and OX2 orexin receptors",
abstract = "We previously demonstrated the potential of di- or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the orexin receptors. In this study we investigated 27 1-benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX1 and two weak dual orexin receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure-activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen-bond acceptors (1-position, benzoyl; 6-position, carboxyl/ester) within 7-8 angstrom of each other; a third acceptor at the 3-position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the orexin receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.",
keywords = "317 Pharmacy, 1-benzoylazulenes, biological activity, drug discovery, medicinal chemistry, orexin receptors, SIGNAL-TRANSDUCTION, CA2+ INFLUX, AZULENE, DERIVATIVES, NONPEPTIDE, PEPTIDE, BINDING, DESIGN, KINASE",
author = "Ainoleena Turku and Leino, {Teppo Olavi} and Karhu, {Lasse Viljami} and Yli-Kauhaluoma, {Jari Tapani} and Kukkonen, {Jyrki Petteri} and Wall{\'e}n, {Erik A. A.} and Xhaard, {Henri Guillaume Michel}",
year = "2019",
month = "5",
day = "6",
doi = "10.1002/cmdc.201900074",
language = "English",
volume = "14",
pages = "965--981",
journal = "ChemMedChem : chemistry enabling drug discovery.",
issn = "1860-7179",
publisher = "Wiley-VCH",
number = "9",

}

TY - JOUR

T1 - Structure-activity relationships of 1-benzoylazulenes at the OX1 and OX2 orexin receptors

AU - Turku, Ainoleena

AU - Leino, Teppo Olavi

AU - Karhu, Lasse Viljami

AU - Yli-Kauhaluoma, Jari Tapani

AU - Kukkonen, Jyrki Petteri

AU - Wallén, Erik A. A.

AU - Xhaard, Henri Guillaume Michel

PY - 2019/5/6

Y1 - 2019/5/6

N2 - We previously demonstrated the potential of di- or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the orexin receptors. In this study we investigated 27 1-benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX1 and two weak dual orexin receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure-activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen-bond acceptors (1-position, benzoyl; 6-position, carboxyl/ester) within 7-8 angstrom of each other; a third acceptor at the 3-position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the orexin receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.

AB - We previously demonstrated the potential of di- or trisubstituted azulenes as ligands (potentiators, weak agonists, and antagonists) of the orexin receptors. In this study we investigated 27 1-benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX1 and two weak dual orexin receptor agonists. For potentiators, replacement of the azulene scaffold by indole retained the activity of four out of six compounds. The structure-activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen-bond acceptors (1-position, benzoyl; 6-position, carboxyl/ester) within 7-8 angstrom of each other; a third acceptor at the 3-position is also well tolerated. The same pharmacophoric signature is found in the preferred conformations of the orexin receptor agonist Nag26 from molecular dynamics simulations. Subtle changes switch the activity between weak agonism and potentiation, suggesting overlapping binding sites.

KW - 317 Pharmacy

KW - 1-benzoylazulenes

KW - biological activity

KW - drug discovery

KW - medicinal chemistry

KW - orexin receptors

KW - SIGNAL-TRANSDUCTION

KW - CA2+ INFLUX

KW - AZULENE

KW - DERIVATIVES

KW - NONPEPTIDE

KW - PEPTIDE

KW - BINDING

KW - DESIGN

KW - KINASE

U2 - 10.1002/cmdc.201900074

DO - 10.1002/cmdc.201900074

M3 - Article

VL - 14

SP - 965

EP - 981

JO - ChemMedChem : chemistry enabling drug discovery.

JF - ChemMedChem : chemistry enabling drug discovery.

SN - 1860-7179

IS - 9

ER -