LAUSR

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 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.