Orexin 2 Receptor
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Orexin receptor type 2 (Ox2R or OX2), also known as hypocretin receptor type 2 (HcrtR2), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the HCRTR2
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.


Structure

The structure of the receptor has been solved to 2.5 Å resolution as a
fusion protein Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this ''fusion gene'' r ...
bound to
suvorexant Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or mainte ...
using lipid-mediated crystallization.


Function

OX2 is a
G-protein coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of protein family, evolution ...
expressed exclusively in the brain. It has 64% identity with OX1. OX2 binds both
orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
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 The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
or
Mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
. This protein has mutations in
Astyanax mexicanus The Mexican tetra (''Astyanax mexicanus''), also known as the blind cave fish, blind cave characin, and blind cave tetra, is a freshwater fish of the family Characidae of the order Characiformes. The type species of its genus, it is native to ...
that reduces the sleep needs of the cavefish.


Ligands


Agonists

*
Danavorexton Danavorexton (developmental code name TAK-925) is a selective orexin 2 receptor agonist. It is a small-molecule compound and is administered intravenously. The compound was found to dose-dependently produce wakefulness to a similar degree as ...
(TAK-925) – selective OX2 receptor agonist * Firazorexton – selective OX2 receptor agonist *
Orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
s – dual OX1 and OX2 receptor agonists **
Orexin-A Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain. Structure Orexin-A is a peptide composed of 33 ...
– approximately equipotent at the OX1 and OX2 receptors **
Orexin-B Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or cataplexy), ...
– 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 * TAK-861 – selective OX2 receptor agonist *
TAK-994 TAK-994 is an orexin receptor agonist which is under development by Takeda for the treatment of narcolepsy. It is a small-molecule and orally active compound and acts as a highly selective agonist of the orexin receptor 2 (OX2) (>700-fold select ...
– selective OX2 receptor agonist


Antagonists

*
Almorexant Almorexant, also known by its development code ACT-078573, is an orexin antagonist, acting as a competitive antagonist of the OX1 and OX2 orexin receptors, which was being developed by the pharmaceutical companies Actelion and GSK for the trea ...
- Dual OX1 and OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
Daridorexant Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth. Side effects of daridorexant include headache, somnolence, and fatigue. The med ...
(nemorexant) - Dual OX1 and OX2 antagonist *
EMPA The Swiss Federal Laboratories for Materials Science and Technology (Empa, German acronym for ''Eidgenössische Materialprüfungs- und Forschungsanstalt'') is an interdisciplinary Swiss research institute for applied materials sciences and tech ...
- Selective OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
Filorexant Filorexant (, ; developmental code name MK-6096) is an orexin antagonist which was under development by Merck for the treatment of insomnia, depression, diabetic neuropathy, and migraine. It is a dual antagonist of the orexin OX1 and OX2 re ...
- Dual OX1 and OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
JNJ-10397049 JNJ-10397049 is a potent and highly selective OX2 receptor antagonist. In animals, JNJ-10397049 was found to have sleep-promoting effects and to attenuate the reinforcing effects of ethanol Ethanol (abbr. EtOH; also called ethyl alcoh ...
(600x selective for OX2 over OX1) *
Lemborexant Lemborexant, sold under the brand name Dayvigo, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or maint ...
- Dual OX1 and OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
* MK-1064 - Selective OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
* MK-8133 - Selective OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
SB-649,868 SB-649868 is a dual orexin receptor antagonist that was being developed by GlaxoSmithKline as a treatment for insomnia. A phase I clinical trial evaluated doses up to 80 mg, resulting in significant improvement in sleep latency without a ...
- Dual OX1 and OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
Seltorexant Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin receptor antagonist, orexin antagonist medication which is under development for the treatment of depression (mood), depression and insomnia. It is a b ...
- Selective OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
Suvorexant Suvorexant, sold under the brand name Belsomra, is an orexin antagonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset and/or mainte ...
- Dual OX1 and OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
*
TCS-OX2-29 TCS-OX2-29 is an orexin antagonist. It was the first non-peptide antagonist developed that is selective for the orexin receptor subtype Hypocretin (orexin) receptor 2, OX2, with an IC50 of 40nM and selectivity of around 250x for OX2 over Hypocret ...
- Selective OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
* (3,4-dimethoxyphenoxy)alkylamino acetamides * Compound 1m - Selective OX2
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...


See also

*
Orexin receptor The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (, ). Both orexin receptors exhibit ...


References


Further reading

* * * * * * * * * * * * * * * * {{Orexin receptor modulators G protein-coupled receptors