Orexin receptor type 2 (Ox2R or OX
2), 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, res ...
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 b ...
.
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
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 evolutionarily-related p ...
expressed exclusively in the brain. It has 64% identity with
OX1. OX
2 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. 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
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 ca ...
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 o ...
. 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 (TAK-925) – selective OX
2 receptor agonist
*
Firazorexton – selective OX
2 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 OX
1 and OX
2 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 ...
– approximately equipotent at the OX
1 and OX
2 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 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
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 OX
2 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 treat ...
- Dual
OX1 and OX
2 antagonist
*
Daridorexant (nemorexant) - Dual OX
1 and OX
2 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 OX
2 antagonist
*
Filorexant - Dual
OX1 and OX
2 antagonist
*
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 alco ...
(600x selective for OX
2 over OX
1)
*
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 OX
2 antagonist
*
MK-1064 - Selective OX
2 antagonist
*
MK-8133 - Selective OX
2 antagonist
*
SB-649,868 - Dual
OX1 and OX
2 antagonist
*
Seltorexant
Seltorexant, also known by its developmental code names MIN-202 and JNJ-42847922, is an orexin antagonist medication which is under development for the treatment of depression and insomnia. It is a selective antagonist of the orexin OX2 recept ...
- Selective OX
2 antagonist
*
Suvorexant - Dual
OX1 and OX
2 antagonist
*
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 OX2, with an IC50 of 40nM and selectivity of around 250x for OX2 over OX1 receptors. Orexin antagonists ar ...
- Selective OX
2 antagonist
* (3,4-dimethoxyphenoxy)alkylamino acetamides
*
Compound 1m - Selective OX
2 antagonist
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
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{{Orexin receptor modulators
G protein-coupled receptors