Orexin receptor

Last updated

hypocretin (orexin) receptor 1
Identifiers
SymbolHCRTR1
NCBI gene 3061
HGNC 4848
OMIM 602392
RefSeq NM_001525
UniProt O43613
Other data
Locus Chr. 1 p33
Search for
Structures Swiss-model
Domains InterPro
hypocretin (orexin) receptor 2
Identifiers
SymbolHCRTR2
NCBI gene 3062
HGNC 4849
OMIM 602393
RefSeq NM_001526
UniProt O43614
Other data
Locus Chr. 6 p11-q11
Search for
Structures Swiss-model
Domains InterPro
Orexin receptor type 2
Identifiers
SymbolOrexin_rec2
Pfam PF03827
InterPro IPR004060
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

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 ( HCRTR1 , HCRTR2 ). [1]

Contents

Both orexin receptors exhibit a similar pharmacology – the 2 orexin peptides, orexin-A and orexin-B, bind to both receptors and, in each case, agonist binding results in an increase in intracellular calcium levels. However, orexin-B shows a 5- to 10-fold selectivity for orexin receptor type 2, whilst orexin-A is equipotent at both receptors. [2] [3]

Several orexin receptor antagonists are in development for potential use in sleep disorders. [4] The first of these, suvorexant, has been on the market in the United States since 2015. [5] There were two orexin agonists under development as of 2019. [6]

Ligands

Several drugs [7] acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia. In August 2015, Nagahara et al. published their work in synthesizing the first HCRT/OX2R agonist, compound 26, with good potency and selectivity. [8]

No neuropeptide 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), [9] two additional agents are in development: SB-649,868 by GlaxoSmithKline, for sleep disorders, and ACT-462206, currently in human clinical trials. [10] Another drug in development, almorexant (ACT-078573) by Actelion, was abandoned due to adverse effects. Lemborexant, 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

Selective

Antagonists

Non-selective

  • Almorexant (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
  • Lemborexant (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 antagonist

Selective

  • ACT-335827 – selective OX1 receptor antagonist
  • AZD-4041 – selective OX1 receptor antagonist [20]
  • C4X-3256 (INDV-2000) – selective OX1 receptor antagonist [21]
  • CVN-766 – selective OX1 receptor antagonist [22]
  • EMPA – selective OX2 receptor antagonist
  • JNJ-10397049 – selective OX2 receptor antagonist
  • Nivasorexant (ACT-539313) – selective OX1 receptor antagonist
  • RTIOX-276 – selective OX1 receptor antagonist
  • SB-334867 – selective OX1 receptor antagonist
  • SB-408124 – selective OX1 receptor antagonist
  • Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX2 receptor antagonist
  • TCS-OX2-29 – selective OX2 receptor antagonist
  • Tebideutorexant (JNJ-61393215; JNJ-3215) – selective OX1 receptor antagonist

Related Research Articles

<span class="mw-page-title-main">Orexin</span> Neuropeptide that regulates arousal, wakefulness, and appetite.

Orexin, also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief losses of muscle tone, is caused by a lack of orexin in the brain due to destruction of the cells that produce it.

<span class="mw-page-title-main">SB-649868</span> Chemical compound

SB-649868 is a dual orexin receptor antagonist that was being developed by GlaxoSmithKline as a treatment for insomnia.

<span class="mw-page-title-main">Hypocretin (orexin) receptor 1</span> Protein-coding gene in the species Homo sapiens

Orexin receptor type 1 (Ox1R or OX1), also known as hypocretin receptor type 1 (HcrtR1), is a protein that in humans is encoded by the HCRTR1 gene.

<span class="mw-page-title-main">Hypocretin (orexin) receptor 2</span> Protein-coding gene in the species Homo sapiens

Orexin receptor type 2 (Ox2R or OX2), also known as hypocretin receptor type 2 (HcrtR2), is a protein that in humans is encoded by the HCRTR2 gene. It should not be confused for the protein CD200R1 which shares the alias OX2R but is a distinct, unrelated gene located on the human chromosome 3.

<span class="mw-page-title-main">Almorexant</span> Orexin antagonist compound

Almorexant (INN), 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 treatment of insomnia. Development of the drug was abandoned in January 2011 due to concerns over the hepatic safety of almorexant after transient increases in liver enzymes were observed in trials.

<span class="mw-page-title-main">Suvorexant</span> Medication used to treat insomnia

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 maintenance in adults. Suvorexant helps with falling asleep faster, sleeping longer, being awake less in the middle of the night, and having better quality of sleep. Its effectiveness is modest, and is similar to that of other orexin antagonists, but is lower than that of benzodiazepines and Z-drugs. Suvorexant is taken by mouth.

An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX1 and OX2. Medical applications include treatment of sleep disorders such as insomnia.

<span class="mw-page-title-main">EMPA (drug)</span> Chemical compound

EMPA is a selective antagonist of the OX2 receptor, with 900-fold selectivity in binding for OX2 over OX1.

<span class="mw-page-title-main">Filorexant</span> Chemical compound

Filorexant (INNTooltip International Nonproprietary Name, USANTooltip United States Approved Name; 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 receptors. It has a relatively short elimination half-life of 3 to 6 hours. However, it dissociates slowly from the orexin receptors and may thereby have a longer duration. Possibly in relation to this, filorexant shows next-day somnolence similarly to suvorexant. In phase 2 clinical trials, filorexant was found to be effective in the treatment of insomnia, but was not effective in the treatment of major depressive disorder, painful diabetic neuropathy, or migraine. As of May 2015, filorexant was no longer listed on Merck's online development pipeline and hence development of the drug appears to have been discontinued. Development of filorexant may have been discontinued due to lack of differentiation from suvorexant (which was also developed by Merck).

<span class="mw-page-title-main">Seltorexant</span> Experimental anti-insomnia drug

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 receptor (2-SORA). The medication is taken by mouth.

<span class="mw-page-title-main">Lemborexant</span> Chemical compound

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 maintenance in adults. The medication is taken by mouth.

<span class="mw-page-title-main">Daridorexant</span> Medication used to treat insomnia

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.

<span class="mw-page-title-main">Danavorexton</span> Chemical compound

Danavorexton 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 modafinil in a phase 1 clinical trial. As of March 2021, danavorexton is under development for the treatment of narcolepsy, idiopathic hypersomnia, and sleep apnea. It is related to another orexin receptor agonist, firazorexton (TAK-994), the development of which was discontinued for safety reasons in October 2021.

<span class="mw-page-title-main">Vornorexant</span> Chemical compound

Vornorexant, also known by its developmental code names ORN-0829 and TS-142, is an orexin antagonist medication which is under development for the treatment of insomnia and sleep apnea. It is a dual orexin OX1 and OX2 receptor antagonist (DORA). The medication is taken by mouth. As of June 2021, vornorexant is in phase 2 clinical trials for insomnia and phase 1 trials for sleep apnea. It is under development by Taisho Pharmaceutical.

<span class="mw-page-title-main">Suntinorexton</span> Chemical compound

Suntinorexton (INNTooltip International Nonproprietary Name; developmental code name TAK-861) is an experimental orexin receptor agonist. It acts as a selective agonist of the orexin OX2 receptor and was described in 2019 in a patent by Takeda Pharmaceutical Company. Suntinorexton superseded firazorexton (TAK-994) as a clinical drug candidate following evidence of hepatoxicity in humans. The drug has reached phase 3 clinical trials as of 2024. It is orally active and centrally penetrant.

<span class="mw-page-title-main">Firazorexton</span> Chemical compound

Firazorexton (INNTooltip International Nonproprietary Name; development code TAK-994) is an experimental orexin 2 (OX2) receptor agonist first described in a 2019 patent filed by Takeda Pharmaceutical Company.

<span class="mw-page-title-main">Fazamorexant</span> Orexin receptor antagonist

Fazamorexant is an orexin receptor antagonist which is under development for the treatment of insomnia. It is taken by mouth.

References

  1. ↑ Spinazzi R, Andreis PG, Rossi GP, Nussdorfer GG (March 2006). "Orexins in the regulation of the hypothalamic-pituitary-adrenal axis". Pharmacological Reviews. 58 (1): 46–57. doi:10.1124/pr.58.1.4. PMID   16507882. S2CID   17941978.
  2. 1 2 3 Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, et al. (September 1999). "Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR". British Journal of Pharmacology. 128 (1): 1–3. doi:10.1038/sj.bjp.0702780. PMC   1571615 . PMID   10498827.
  3. 1 2 3 Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ (January 2004). "Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor". British Journal of Pharmacology. 141 (2): 340–346. doi:10.1038/sj.bjp.0705610. PMC   1574197 . PMID   14691055.
  4. ↑ Yin J, Mobarec JC, Kolb P, Rosenbaum DM (March 2015). "Crystal structure of the human OX2 orexin receptor bound to the insomnia drug suvorexant". Nature. 519 (7542): 247–250. doi:10.1038/nature14035. PMID   25533960. S2CID   4405254.
  5. ↑ "Merck's Insomnia Medicine Belsomra C-IV Now Available in US". Sleep Review. 3 February 2015. Retrieved 2019-12-06.
  6. ↑ "New Data Presented at World Sleep Congress Demonstrate Early Signs of Efficacy for TAK-925, a Selective Orexin Type-2 Receptor (OX2R) Agonist, in Patients with Narcolepsy Type 1". www.takeda.com. Retrieved 2019-12-06.
  7. ↑ Heifetz A, Morris GB, Biggin PC, Barker O, Fryatt T, Bentley J, et al. (April 2012). "Study of human Orexin-1 and -2 G-protein-coupled receptors with novel and published antagonists by modeling, molecular dynamics simulations, and site-directed mutagenesis". Biochemistry. 51 (15): 3178–3197. doi:10.1021/bi300136h. PMID   22448975. S2CID   42765328.
  8. ↑ Chow M, Cao M (2016). "The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress". Nature and Science of Sleep. 8: 81–86. doi: 10.2147/NSS.S76711 . PMC   4803263 . PMID   27051324.
  9. ↑ Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, et al. (2011). "The First Large-Scale Synthesis of MK-4305: A Dual Orexin Receptor Antagonist for the Treatment of Sleep Disorder". Organic Process Research & Development. 15 (2): 367–375. doi:10.1021/op1002853.
  10. ↑ Hoch M, van Gorsel H, van Gerven J, Dingemanse J (September 2014). "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant". Journal of Clinical Pharmacology. 54 (9): 979–986. doi:10.1002/jcph.297. PMID   24691844. S2CID   40714628.
  11. ↑ "AEX 5". AdisInsight. Springer Nature Switzerland AG. 12 March 2024. Retrieved 31 July 2024.
  12. ↑ "AEX 19". AdisInsight. Springer Nature Switzerland AG. 22 March 2024. Retrieved 31 July 2024.
  13. ↑ "NLS Pharmaceutics licenses Aexon's dual orexin receptor agonists". BioWorld. 31 July 2024. Retrieved 31 July 2024. [...] AEX-5, an OX1R agonist, cathepsin H inhibitor and DAT reuptake inhibitor; and AEX-24, which acts as an S1R agonist and OX2R agonist. [...]
  14. ↑ "ALKS 2680". AdisInsight. Springer Nature Switzerland AG. 7 June 2024. Retrieved 31 July 2024.
  15. ↑ "E-2086". AdisInsight. Springer Nature Switzerland AG. 15 July 2024. Retrieved 31 July 2024.
  16. 1 2 "WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 : International Nonproprietary Names for Pharmaceutical Substances (INN)" (PDF). Who.int. Retrieved 1 December 2021.
  17. 1 2 WOapplication 2019027058,Kajita Y, Mikami SM Miyanohana Y, Koike T, Daini M, Oyabu N, Ogino M, Takeuchi K, Ito Y, Tokunaga N, Sugimoto T, Miyazaki T, Oda T, Hoashi Y, Hattori Y, Imamura K,"Heterocyclic compound and use therof",published 2019-02-07, assigned to Takeda Pharmaceutical Company
  18. ↑ "Wave 1 Pipeline Market Opportunity Conference Call" (PDF). Takeda Pharmaceutical Company Limited. 8 December 2020. Archived from the original (PDF) on 2021-10-20. TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20
  19. ↑ Prischich D, Sortino R, Gomila-Juaneda A, Matera C, Guardiola S, Nepomuceno D, et al. (July 2024). "In vivo photocontrol of orexin receptors with a nanomolar light-regulated analogue of orexin-B". Cellular and Molecular Life Sciences. 81 (1): 288. doi:10.1007/s00018-024-05308-x. PMC   11335211 . PMID   38970689.
  20. ↑ "AZD 4041". AdisInsight. Springer Nature Switzerland AG. 31 May 2024. Retrieved 31 July 2024.
  21. ↑ "C4X 3256". AdisInsight. Springer Nature Switzerland AG. 13 June 2024. Retrieved 31 July 2024.
  22. ↑ "CVN 766". AdisInsight. Springer Nature Switzerland AG. 16 February 2023. Retrieved 31 July 2024.
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