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]
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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[update].[6]
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
- Orexins – dual OX1 and OX2 receptor agonists
- Orexin-A – approximately equipotent at the OX1 and OX2 receptors[2][3]
- Orexin-B – approximately 5- to 10-fold selectivity for the OX2 receptor over the OX1 receptor[2][3]
- AEX-5 – selective OX1 receptor agonist; also a cathepsin H inhibitor and dopamine reuptake inhibitor[11]
- AEX-19 – dual OX1 and OX2 receptor agonist[12]
- AEX-24 – selective OX1 receptor agonist; also an "S1R" agonist[13]
Selective
- ALKS-2680 — selective oral OX2 receptor agonist[14]
- Danavorexton (TAK-925) – selective OX2 receptor agonist
- E-2086 – selective OX2 receptor agonist[15]
- Firazorexton (TAK-994) – selective OX2 receptor agonist[16][17]
- Oveporexton – selective OX2 receptor agonist
- SB-668875 – selective OX2 receptor agonist
- Suntinorexton (TAK-861) – selective OX2 receptor agonist[16][17][18]
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[19]
- C4X-3256 (INDV-2000) – selective OX1 receptor antagonist[20]
- CVN-766 – selective OX1 receptor antagonist[21]
- 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
Yin J, Mobarec JC, Kolb P, Rosenbaum DM (December 2014). "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.
Heifetz A, Morris GB, Biggin PC, Barker O, Fryatt T, Bentley J, Hallett D, Manikowski DP, Pal S, Reifegerste R, Slack M, Law R (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.
Baxter CA, Cleator ED, Karel MJ, Edwards JS, Reamer RA, Sheen FJ, Stewart GW, Strotman NA, Wallace DJ (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.
Hoch M, van Gorsel H, van Gerven J, Dingemanse J (Sep 2014). "Entry-into-humans study with ACT-462206, a novel dual orexin receptor antagonist, comparing its pharmacodynamics with almorexant". J Clin Pharmacol. 54 (9): 979–86. doi:10.1002/jcph.297. PMID 24691844. S2CID 40714628.
"AEX 5". AdisInsight. 12 March 2024. Retrieved 31 July 2024.
"AEX 19". AdisInsight. 22 March 2024. Retrieved 31 July 2024.
"ALKS 2680". AdisInsight. 7 June 2024. Retrieved 31 July 2024.
"E-2086". AdisInsight. 15 July 2024. Retrieved 31 July 2024.
"AZD 4041". AdisInsight. 31 May 2024. Retrieved 31 July 2024.
"C4X 3256". AdisInsight. 13 June 2024. Retrieved 31 July 2024.
"CVN 766". AdisInsight. 16 February 2023. Retrieved 31 July 2024.