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 OX1/2R 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.