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In this study we investigated 27 1\u2010benzoylazulene derivatives, uncovering seven potentiators of the orexin response on OX<jats:sub>1<\/jats:sub> 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\u2013activity relationships for agonism and potentiation can be summarized into a bicyclic aromatic ring system substituted with two hydrogen\u2010bond acceptors (1\u2010position, benzoyl; 6\u2010position, carboxyl\/ester) within 7\u20138\u2005\u00c5 of each other; a third acceptor at the 3\u2010position 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.<\/jats:p>","DOI":"10.1002\/cmdc.201900074","type":"journal-article","created":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T07:53:56Z","timestamp":1553068436000},"page":"965-981","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Structure\u2013Activity Relationships of 1\u2010Benzoylazulenes at the OX<sub>1<\/sub> and OX<sub>2<\/sub> Orexin Receptors"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0959-7221","authenticated-orcid":false,"given":"Ainoleena","family":"Turku","sequence":"first","affiliation":[{"name":"Drug Research Program Division of Pharmaceutical Chemistry and Technology Faculty of Pharmacy University of Helsinki  P.O. 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