Design and Synthesis of Orexin 1 Receptor-Selective Agonists
Keita Iio, Kao Hashimoto, Yasuyuki Nagumo, Mao Amezawa, Taisei Hasegawa, Naoshi Yamamoto, Noriki Kutsumura, Katsuhiko Takeuchi, Yukiko Ishikawa, Hikari Yamamoto, Akihisa Tokuda, Tetsu Sato, Yasuo Uchida, Asuka Inoue, Ryuji Tanimura, Masashi Yanagisawa, Hiroshi Nagase, Tsuyoshi Saitoh
Abstract
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 (OX 1 R) and orexin 2 receptors (OX 2 R). Since the discovery that dysfunction of the orexin/OX 2 R system causes the sleep disorder narcolepsy, several OX 2 R-selective and OX 1/2 R dual agonists have been disclosed. However, an OX 1 R-selective agonist has not yet been reported, despite the importance of the biological function of OX 1 R. Herein, we report the discovery of a potent OX 1 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; EC 50 = 7.48 nM for OX 1 R; OX 2 R/OX 1 R EC 50 ratio = 22.5]. The OX 1 R-selective agonist ( R )-YNT-3708 exhibited antinociceptive and reinforcing effects through the activation of OX 1 R in mice.