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 (OX1 R) and orexin 2 receptors (OX2 R). Since the discovery that dysfunction of the orexin/OX2 R system causes the sleep disorder narcolepsy, several OX2 R-selective and OX1/2 R dual agonists have been disclosed. However, an OX1 R-selective agonist has not yet been reported, despite the importance of the biological function of OX1 R. Herein, we report the discovery of a potent OX1 R-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 OX1 R; OX2 R/OX1 R EC50 ratio = 22.5]. The OX1 R-selective agonist ( R )-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX1 R in mice.