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Design and Synthesis of Orexin 1 Receptor-Selective Agonists

Keita Iio1,2, Kao Hashimoto1,3, Yasuyuki Nagumo1

  • 1International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.

Journal of Medicinal Chemistry
|April 12, 2023
PubMed

Insights

Researchers discovered a novel orexin 1 receptor (OX1R) selective agonist, (R)-YNT-3708. This potent compound shows promise for targeting OX1R-related functions and behaviors in preclinical models.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Orexins are neuropeptides regulating sleep, emotion, and feeding via OX1R and OX2R.
  • Orexin/OX2R system dysfunction is linked to narcolepsy, leading to OX2R-selective and dual agonists.
  • No selective OX1R agonist had been reported despite OX1R's biological importance.

Purpose of the Study:

  • To discover and characterize a potent and selective OX1R agonist.
  • To investigate the potential therapeutic applications of selective OX1R activation.

Main Methods:

  • Synthesis and in vitro characterization of (R)-YNT-3708.
  • Assay of OX1R and OX2R binding and functional activity (EC50 values).
  • In vivo assessment of antinociceptive and reinforcing effects in mice.

Main Results:

  • Discovery of (R)-YNT-3708, a potent OX1R-selective agonist (EC50 = 7.48 nM).
  • High selectivity for OX1R over OX2R (OX2R/OX1R EC50 ratio = 22.5).
  • Demonstrated antinociceptive and reinforcing effects mediated by OX1R activation in mice.

Conclusions:

  • (R)-YNT-3708 represents the first potent and selective OX1R agonist.
  • This discovery opens avenues for exploring OX1R's role in various physiological processes.
  • Selective OX1R agonists may offer therapeutic potential for conditions involving pain and reward pathways.

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