The orexin receptor (also referred to as the hypocretin receptor) 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 ...

that binds the neuropeptide

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) ...

. There are two variants, OX₁ and OX₂, each encoded by a different gene (, ). Both orexin receptors exhibit a similar pharmacology – the 2 orexin peptides,

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 ...

and

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) ...

, bind to both

receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...

and, in each case, agonist binding results in an increase in

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...

levels. However, orexin-B shows a 5- to 10-fold selectivity for orexin receptor type 2, whilst orexin-A is equipotent at both receptors. Several

orexin receptor antagonist An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders s ...

s are in development for potential use in sleep disorders. The first of these, suvorexant, has been on the market in the United States since 2015. There were two orexin agonists under development .

Ligands

Several drugs acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as

narcolepsy Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...

, or orexin antagonists for

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

. In August 2015, Nagahara et al. published their work in synthesizing the first HCRT/OX2R agonist, compound 26, with good potency and selectivity. No

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

agonists are yet available, although synthetic orexin-A polypeptide has been made available as a nasal spray and tested on monkeys. One non-peptide antagonist is currently available in the U.S., Merck's suvorexant (Belsomra), two additional agents are in development: SB-649,868 by GlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials. Another drug in development,

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 ...

(ACT-078573) by Actelion, was abandoned due to adverse effects.

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 ...

, an orexin receptor antagonist, was approved for use in the United States in 2019. Most ligands acting on the orexin system so far are polypeptides modified from the endogenous agonists orexin-A and orexin-B, however there are some subtype-selective non-peptide antagonists available for research purposes.

Agonists

Non-selective

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 ...

– 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

Selective

* Danavorexton (TAK-925) – selective OX₂ receptor agonist * Firazorexton – selective OX₂ receptor agonist * 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

Non-selective

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 ...

(ACT-078573) – dual OX₁ and OX₂ receptor antagonist * Daridorexant (Quviviq; ACT-541468) – dual OX₁ and OX₂ receptor antagonist * Filorexant (MK-6096) – dual OX₁ and OX₂ receptor antagonist * GSK-649868 (SB-649868) – dual OX₁ and OX₂ receptor antagonist *

(Dayvigo) – dual OX₁ and OX₂ receptor antagonist * Suvorexant (Belsomra) – dual OX₁ and OX₂ receptor antagonist * Vornorexant (ORN-0829, TS-142) – dual OX₁ and OX₂ receptor agonist

Selective

* ACT-335827 – selective OX₁ receptor 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 receptor 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 ...

– selective OX₂ receptor antagonist * RTIOX-276 – selective OX₁ receptor antagonist * SB-334867 – selective OX₁ receptor antagonist *

SB-408124 SB-408124 is a drug which is a non-peptide antagonist selective for the orexin receptor subtype OX1, with around 70x selectivity for OX1 over OX2 receptors, and improved oral bioavailability compared to the older OX1 antagonist SB-334867. It ...

– selective OX₁ receptor antagonist * Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX₂ receptor 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 OX₂ receptor antagonist

References

External links

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