Hypocretin (orexin) receptor 2
# Hypocretin (orexin) receptor 2

Orexin receptor type 2 (Ox2R or $OX_2),$ also known as hypocretin receptor type 2 (HcrtR2), is a protein that in humans is encoded by the HCRTR2 gene.

## 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

$OX_2$ is a G-protein coupled receptor expressed exclusively in the brain. It has 64% identity with $OX_1.$ $OX_2$ binds both orexin A and orexin B neuropeptides. $OX_2$ is involved in the central feedback mechanism that regulates feeding behaviour. Mice with enhanced $OX_2$ 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 $OX_2$ receptor agonist
* Firazorexton – selective $OX_2$ receptor agonist
* Orexins – dual $OX_1$ and $OX_2$ receptor agonists
   * Orexin-A – approximately equipotent at the $OX_1$ and $OX_2$ receptors
   * Orexin-B – approximately 5- to 10-fold selectivity for the $OX_2$ receptor over the $OX_1$ receptor
* SB-668875 – selective $OX_2$ receptor agonist
* Suntinorexton – selective $OX_2$ receptor agonist
* TAK-861 – selective $OX_2$ receptor agonist
* TAK-994 – selective $OX_2$ receptor agonist

### Antagonists

* Almorexant - Dual $OX_1$ and $OX_2$ antagonist
* Daridorexant (nemorexant) - Dual $OX_1$ and $OX_2$ antagonist
* EMPA - Selective $OX_2$ antagonist
* Filorexant - Dual $OX_1$ and $OX_2$ antagonist
* JNJ-10397049 (600x selective for $OX_2$ over $OX_1)$
* Lemborexant - Dual $OX_1$ and $OX_2$ antagonist
* MK-1064 - Selective $OX_2$ antagonist
* MK-8133 - Selective $OX_2$ antagonist
* SB-649,868 - Dual $OX_1$ and $OX_2$ antagonist
* Seltorexant - Selective $OX_2$ antagonist
* Suvorexant - Dual $OX_1$ and $OX_2$ antagonist
* TCS-OX2-29 - Selective $OX_2$ antagonist
* (3,4-dimethoxyphenoxy)alkylamino acetamides
* Compound 1m - Selective $OX_2$ antagonist
