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Design and Synthesis of Orexin 1 Receptor-Selective Agonists

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JOURNAL OF MEDICINAL CHEMISTRY
卷 66, 期 8, 页码 5453-5464

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AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01773

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Orexins are neuropeptides that regulate sleep, emotion, and feeding. We discovered a potent OX1R-selective agonist and demonstrated its antinociceptive and reinforcing effects in mice.
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-m ethylacet amido)-5, 6, 7, 8-tetrahydro-naphthalen-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.

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