Orexin receptor

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hypocretin (orexin) receptor 1
Identifiers
Symbol HCRTR1
Entrez 3061
HUGO 4848
OMIM 602392
RefSeq NM_001525
UniProt O43613
Other data
Locus Chr. 1 p33
hypocretin (orexin) receptor 2
Identifiers
Symbol HCRTR2
Entrez 3062
HUGO 4849
OMIM 602393
RefSeq NM_001526
UniProt O43614
Other data
Locus Chr. 6 p11-q11
Orexin receptor type 2
Identifiers
Symbol Orexin_rec2
Pfam PF03827
InterPro IPR004060

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]

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 10-fold selectivity for orexin receptor type 2, whilst orexin-A is equipotent at both receptors.[2]

Several orexin receptor antagonists are in development for potential use in sleep disorders. Only the crystal structure of OX2 is known.[3]

Selective ligands

Several drugs[4] acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia. No non-peptide agonists are yet available, although synthetic Orexin-A polypeptide has been made available as a nasal spray and tested on monkeys. Several non-peptide antagonists are in development however; SB-649,868 by GlaxoSmithKline for sleep disorders is a non-selective orexin receptor antagonist. Another dual orexin antagonist, almorexant (ACT-078573) by Actelion, was abandoned because of side effects. A third entry is Merck's suvorexant (Belsomra),[5] which has recently been approved for use. A new antagonist compound, ACT-462206, was recently studied in humans.[6]

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.

  • SB-334,867 – selective OX1 antagonist
  • SB-408,124 – selective OX1 antagonist
  • TCS-OX2-29 – selective OX2 antagonist
  • EMPA (N-Ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) – selective OX2 antagonist
  • RTIOX-276 – selective OX1 antagonist

References

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External links

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This article incorporates text from the public domain Pfam and InterPro IPR004060