Hypocretin (orexin) receptor 2

Structure

The structure of the receptor has been solved to 2.5 Å resolution as a fusion protein bound to suvorexant using lipid-mediated crystallization.

Function

OX2 is a G-protein coupled receptor expressed exclusively in the brain. It has 64% identity with OX1. OX2 binds both orexin A and orexin B neuropeptides. OX2 is involved in the central feedback mechanism that regulates feeding behaviour. Mice with enhanced OX2 signaling are resistant to high-fat diet-induced obesity.

This receptor is activated by Hipocretin, which is a wake-promoting hypothalamic neuropeptide that acts as a critical regulator of sleep in animals as Zebrafish or Mammals. This protein has mutations in Astyanax mexicanus that reduces the sleep needs of the cavefish.

Ligands

Agonists

• Danavorexton/TAK-925 – selective OX2 receptor agonist
• Firazorexton/TAK-994 – selective OX2 receptor agonist
• Orexins – dual OX1 and OX2 receptor agonists
  • Orexin-A – approximately equipotent at the OX1 and OX2 receptors
  • Orexin-B – approximately 5- to 10-fold selectivity for the OX2 receptor over the OX1 receptor
• SB-668875 – selective OX2 receptor agonist
• Suntinorexton – selective OX2 receptor agonist
• Oveporexton/TAK-861 – selective OX2 receptor agonist

Antagonists

• Almorexant - Dual OX1 and OX2 antagonist
• Daridorexant (nemorexant) - Dual OX1 and OX2 antagonist
• EMPA - Selective OX2 antagonist
• Filorexant - Dual OX1 and OX2 antagonist
• JNJ-10397049 (600x selective for OX2 over OX1)
• Lemborexant - Dual OX1 and OX2 antagonist
• MK-1064 - Selective OX2 antagonist
• MK-8133 - Selective OX2 antagonist
• SB-649,868 - Dual OX1 and OX2 antagonist
• Seltorexant - Selective OX2 antagonist
• Suvorexant - Dual OX1 and OX2 antagonist
• TCS-OX2-29 - Selective OX2 antagonist
• (3,4-dimethoxyphenoxy)alkylamino acetamides
• Compound 1m - Selective OX2 antagonist

References

References

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12. (February 2014). "Discovery of 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia". ChemMedChem.
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