Hypocretin (orexin) receptor 2 explained

Symbol:	Orexin_rec2
Orexin receptor type 2
Pfam:	PF03827
Interpro:	IPR004060

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.^[1] 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.^[2]

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.^[3]

Function

OX₂ is a G-protein coupled receptor expressed exclusively in the brain. It has 64% identity with OX₁. OX₂ binds both orexin A and orexin B neuropeptides. OX₂ is involved in the central feedback mechanism that regulates feeding behaviour.^[1] Mice with enhanced OX₂ signaling are resistant to high-fat diet-induced obesity.^[4]

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 or Mammals. This protein has mutations in Astyanax mexicanus that reduces the sleep needs of the cavefish. ^[5]

Ligands

Agonists

• Danavorexton (TAK-925) – selective OX₂ receptor agonist
• Firazorexton – selective OX₂ receptor agonist^[6]
• Orexins – dual OX₁ and OX₂ receptor agonists
  • Orexin-A – approximately equipotent at the OX₁ and OX₂ receptors^{[7] [8]}
  • Orexin-B – approximately 5- to 10-fold selectivity for the OX₂ receptor over the OX₁ receptor
• Oveporexton
• SB-668875 – selective OX₂ receptor agonist
• Suntinorexton – selective OX₂ receptor agonist
• TAK-861 – selective OX₂ receptor agonist^[9]

Antagonists

• Almorexant - Dual OX₁ and OX₂ antagonist
• Daridorexant (nemorexant) - Dual OX₁ and OX₂ antagonist
• EMPA - Selective OX₂ antagonist
• Filorexant - Dual OX₁ and OX₂ antagonist
• JNJ-10397049 (600x selective for OX₂ over OX₁)^[10]
• Lemborexant - Dual OX₁ and OX₂ antagonist
• MK-1064 - Selective OX₂ antagonist^[11]
• MK-8133 - Selective OX₂ antagonist^[12]
• SB-649,868 - Dual OX₁ and OX₂ antagonist
• Seltorexant - Selective OX₂ antagonist
• Suvorexant - Dual OX₁ and OX₂ antagonist
• TCS-OX2-29 - Selective OX₂ antagonist
• (3,4-dimethoxyphenoxy)alkylamino acetamides^[13]
• Compound 1m - Selective OX₂ antagonist^[14]

See also

• Orexin receptor

Further reading

• Flier JS, Maratos-Flier E . Obesity and the hypothalamus: novel peptides for new pathways . Cell . 92 . 4 . 437–440 . February 1998 . 9491885 . 10.1016/S0092-8674(00)80937-X . 14768585 . free .
• Willie JT, Chemelli RM, Sinton CM, Yanagisawa M . To eat or to sleep? Orexin in the regulation of feeding and wakefulness . Annual Review of Neuroscience . 24 . 429–458 . 2001 . 11283317 . 10.1146/annurev.neuro.24.1.429 .
• Hungs M, Mignot E . Hypocretin/orexin, sleep and narcolepsy . BioEssays . 23 . 5 . 397–408 . May 2001 . 11340621 . 10.1002/bies.1058 . 541650 .
• de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG . The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity . Proceedings of the National Academy of Sciences of the United States of America . 95 . 1 . 322–327 . January 1998 . 9419374 . 18213 . 10.1073/pnas.95.1.322 . free . 1998PNAS...95..322D .
• Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M . Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior . Cell . 92 . 4 . 573–585 . February 1998 . 9491897 . 10.1016/S0092-8674(00)80949-6 . 16294729 . free .
• Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M . Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior . Cell . 92 . 5 . 1 page following 696 . March 1998 . 9527442 . 10.1016/S0092-8674(02)09256-5 . free .
• Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E . A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains . Nature Medicine . 6 . 9 . 991–997 . September 2000 . 10973318 . 10.1038/79690 . 18076282 .
• Wright GJ, Puklavec MJ, Willis AC, Hoek RM, Sedgwick JD, Brown MH, Barclay AN . Lymphoid/neuronal cell surface OX2 glycoprotein recognizes a novel receptor on macrophages implicated in the control of their function . Immunity . 13 . 2 . 233–242 . August 2000 . 10981966 . 10.1016/S1074-7613(00)00023-6 . free .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–1795 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Mazzocchi G, Malendowicz LK, Gottardo L, Aragona F, Nussdorfer GG . Orexin A stimulates cortisol secretion from human adrenocortical cells through activation of the adenylate cyclase-dependent signaling cascade . The Journal of Clinical Endocrinology and Metabolism . 86 . 2 . 778–782 . February 2001 . 11158046 . 10.1210/jcem.86.2.7233 . free .
• Blanco M, López M, García-Caballero T, Gallego R, Vázquez-Boquete A, Morel G, Señarís R, Casanueva F, Diéguez C, Beiras A . Cellular localization of orexin receptors in human pituitary . The Journal of Clinical Endocrinology and Metabolism . 86 . 4 . 1616–1619 . April 2001 . 10.1210/jcem.86.7.7433 . 11297593 . free .
• Blanco M, López M, GarcIa-Caballero T, Gallego R, Morel G, SeñarIs R, Casanueva F, Diéguez C, Beiras A . Cellular localization of orexin receptors in human pituitary . The Journal of Clinical Endocrinology and Metabolism . 86 . 7 . 1616–1619 . July 2001 . 10.1210/jcem.86.7.7433 . 11443222 . free .
• Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW . Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals . The Journal of Clinical Endocrinology and Metabolism . 86 . 9 . 4512–4519 . September 2001 . 11549701 . 10.1210/jcem.86.9.7849 . free .
• Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW . Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis . The Journal of Clinical Endocrinology and Metabolism . 86 . 10 . 4808–4813 . October 2001 . 11600545 . 10.1210/jcem.86.10.7921 . free .
• Olafsdóttir BR, Rye DB, Scammell TE, Matheson JK, Stefánsson K, Gulcher JR . Polymorphisms in hypocretin/orexin pathway genes and narcolepsy . Neurology . 57 . 10 . 1896–1899 . November 2001 . 11723285 . 10.1212/wnl.57.10.1896 . 38597998 .
• Blanco M, García-Caballero T, Fraga M, Gallego R, Cuevas J, Forteza J, Beiras A, Diéguez C . Cellular localization of orexin receptors in human adrenal gland, adrenocortical adenomas and pheochromocytomas . Regulatory Peptides . 104 . 1–3 . 161–165 . March 2002 . 11830291 . 10.1016/S0167-0115(01)00359-7 . 30238394 .

Notes and References

1. Web site: Entrez Gene: HCRTR2 hypocretin (orexin) receptor 2.
2. Web site: Genecards CD200R1 . 2024-07-17.
3. Liszewski. Kathy. 1 October 2015. Dissecting the Structure of Membrane Proteins. Genetic Engineering & Biotechnology News. 35. 17. 16. 10.1089/gen.35.07.09.
4. Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, Yanagisawa M . Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity . Cell Metabolism . 9 . 1 . 64–76 . January 2009 . 19117547 . 2630400 . 10.1016/j.cmet.2008.10.010 .
5. Warren WC, Boggs TE, Borowsky R, Carlson BM, Ferrufino E, Gross JB, Hillier L, Hu Z, Keene AC, Kenzior A, Kowalko JE, Tomlinson C, Kremitzki M, Lemieux ME, Graves-Lindsay T, McGaugh SE, Miller JT, Mommersteeg MT, Moran RL, Peuß R, Rice ES, Riddle MR, Sifuentes-Romero I, Stanhope BA, Tabin CJ, Thakur S, Yamamoto Y, Rohner N . A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution . Nature Communications . 12 . 1 . 1447 . March 2021 . 33664263 . 7933363 . 10.1038/s41467-021-21733-z . 2021NatCo..12.1447W .
6. Web site: WHO Drug Information, Vol. 34, No. 2, 2020 Proposed INN: List 123 263 : International Nonproprietary Names for Pharmaceutical Substances (INN). Who.int. 2021-11-30.
7. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F . Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR . British Journal of Pharmacology . 128 . 1 . 1–3 . September 1999 . 10498827 . 1571615 . 10.1038/sj.bjp.0702780 .
8. Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ . 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 . January 2004 . 14691055 . 1574197 . 10.1038/sj.bjp.0705610 .
9. Web site: Wave 1 Pipeline Market Opportunity Conference Call . TAK-861, a second oral OX2R agonist will begin clinical testing in 2H FY20 . Takeda Pharmaceutical Company Limited . 8 December 2020 . https://web.archive.org/web/20211020015502/https://fs2.magicalir.net/tdnet/2020/4502/20201208432630.pdf . 2021-10-20 .
10. McAtee LC, Sutton SW, Rudolph DA, Li X, Aluisio LE, Phuong VK, Dvorak CA, Lovenberg TW, Carruthers NI, Jones TK . Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX(2)R) antagonists . Bioorganic & Medicinal Chemistry Letters . 14 . 16 . 4225–4229 . August 2004 . 15261275 . 10.1016/j.bmcl.2004.06.032 .
11. Roecker AJ, Mercer SP, Schreier JD, Cox CD, Fraley ME, Steen JT, Lemaire W, Bruno JG, Harrell CM, Garson SL, Gotter AL, Fox SV, Stevens J, Tannenbaum PL, Prueksaritanont T, Cabalu TD, Cui D, Stellabott J, Hartman GD, Young SD, Winrow CJ, Renger JJ, Coleman PJ . Discovery of 5-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3-terpyridine-3'-carboxamide (MK-1064): a selective orexin 2 receptor antagonist (2-SORA) for the treatment of insomnia . ChemMedChem . 9 . 2 . 311–322 . February 2014 . 24376006 . 10.1002/cmdc.201300447 . 26114114 .
12. Kuduk SD, Skudlarek JW, DiMarco CN, Bruno JG, Pausch MH, O'Brien JA, Cabalu TD, Stevens J, Brunner J, Tannenbaum PL, Garson SL, Savitz AT, Harrell CM, Gotter AL, Winrow CJ, Renger JJ, Coleman PJ . Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties . Bioorganic & Medicinal Chemistry Letters . 25 . 12 . 2488–2492 . June 2015 . 25981685 . 10.1016/j.bmcl.2015.04.066 .
13. Cole AG, Stroke IL, Qin LY, Hussain Z, Simhadri S, Brescia MR, Waksmunski FS, Strohl B, Tellew JE, Williams JP, Saunders J, Appell KC, Henderson I, Webb ML . Synthesis of (3,4-dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists . Bioorganic & Medicinal Chemistry Letters . 18 . 20 . 5420–5423 . October 2008 . 18815029 . 10.1016/j.bmcl.2008.09.038 .
14. Fujimoto T, Kunitomo J, Tomata Y, Nishiyama K, Nakashima M, Hirozane M, Yoshikubo S, Hirai K, Marui S . Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists . Bioorganic & Medicinal Chemistry Letters . 21 . 21 . 6414–6416 . November 2011 . 21917455 . 10.1016/j.bmcl.2011.08.093 .