Symbol HCRTR1 HUGO 4848 RefSeq NM_001525 | Entrez 3061 OMIM 602392 UniProt O43613 | |
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).
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.
Several orexin receptor antagonists are in development for potential use in sleep disorders. Only the crystal structure of OX2 is known.
Selective ligands
Several drugs 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), which has recently been approved for use. A new antagonist compound, ACT-462206, was recently studied in humans.
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.