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Structure-Activity Relationships of 1-Benzoylazulenes at the OX1 and OX2 Orexin Receptors.
Turku, Ainoleena; Leino, Teppo O; Karhu, Lasse; Yli-Kauhaluoma, Jari; Kukkonen, Jyrki P; Wallén, Erik A A; Xhaard, Henri.
Afiliación
  • Turku A; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
  • Leino TO; Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, 00014, Helsinki, Finland.
  • Karhu L; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
  • Yli-Kauhaluoma J; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
  • Kukkonen JP; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
  • Wallén EAA; Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 66, 00014, Helsinki, Finland.
  • Xhaard H; Department of Physiology, Faculty of Medicine, University of Helsinki, P.O. Box 63, 00014, Helsinki, Finland.
ChemMedChem ; 14(9): 965-981, 2019 05 06.
Article en En | MEDLINE | ID: mdl-30892823
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 Šof 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azulenos / Receptores de Orexina Límite: Animals / Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Alemania
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azulenos / Receptores de Orexina Límite: Animals / Humans Idioma: En Revista: ChemMedChem Asunto de la revista: FARMACOLOGIA / QUIMICA Año: 2019 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Alemania