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 (OXR) and orexin 2 receptors (OXR). Since the discovery that dysfunction of the orexin/OXR system causes the sleep disorder narcolepsy, several OXR-selective and OXR dual agonists have been disclosed. However, an OXR-selective agonist has not yet been reported, despite the importance of the biological function of OXR. Herein, we report the discovery of a potent OXR-selective agonist, (,)-3-(4-methoxy-3-(-(8-(2-(3-methoxyphenyl)--methylacetamido)-5,6,7,8-tetrahydronaphthalen-2-yl)sulfamoyl)phenyl)--(pyridin-4-yl)acrylamide [()-YNT-3708; EC = 7.48 nM for OXR; OXR/OXR EC ratio = 22.5]. The OXR-selective agonist ()-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OXR in mice.