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Structure–Activity Relationships of 1‐Benzoylazulenes at the OX 1 and OX 2 Orexin Receptors
Author(s) -
Turku Ainoleena,
Leino Teppo O.,
Karhu Lasse,
YliKauhaluoma Jari,
Kukkonen Jyrki P.,
Wallén Erik A. A.,
Xhaard Henri
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900074
Subject(s) - potentiator , chemistry , orexin , stereochemistry , long term potentiation , agonist , receptor , orexin receptor , indole test , pharmacology , biochemistry , neuropeptide , medicine
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 OX 1 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 Å 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.