Design and Synthesis of Orexin 1 Receptor-Selective Agonists

Orexins are a family of neuropeptides that regulate various physiological events, such as sleep/wakefulness as well as emotional and feeding behavior, and that act on two G-protein-coupled receptors, i.e., orexin 1 (OX₁R) and orexin 2 receptors (OX₂R). Since the discovery that dysfunction of the orexin/OX₂R system causes the sleep disorder narcolepsy, several OX₂R-selective and OX_1/2R dual agonists have been disclosed. However, an OX₁R-selective agonist has not yet been reported, despite the importance of the biological function of OX₁R. Herein, we report the discovery of a potent OX₁R-selective agonist, (R,E)-3-(4-methoxy-3-(N-(8-(2-(3-methoxyphenyl)-N-methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)-N-(pyridin-4-yl)acrylamide [(R)-YNT-3708; EC₅₀ = 7.48 nM for OX₁R; OX₂R/OX₁R EC₅₀ ratio = 22.5]. The OX₁R-selective agonist (R)-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX₁R in mice.