Orexin Receptors

Orexin-A and orexin-B are 33- and 28-residue peptides, respectively, that were originally isolated from the rat hypothalamus. Orexin-A contains an amidated carboxy terminus, a cyclized pyroglutaminyl residue at the amino terminus and two intramolecular disulfide bridges between Cys6-Cys12 and Cys7-Cys14. Orexin-B is amidated at its carboxy terminus and shares 46% amino acid identity with orexin-A. Both peptides are derived by proteolytic cleavage from a 130 amino acid precursor, prepro-orexin, which is encoded by a gene localized to chromosome 17q21 in humans. Orexin-A is fully conserved across mammalian species, while rat and human orexin-B differ by two amino acids. Both peptides bind to two G protein-coupled receptors, termed OX1 and OX2, and mediate increases in intracellular calcium concentrations. The receptors display 64% homology, are most closely related (26%) to the Y2 neuropeptide Y receptor and are highly conserved across species, with a 94% homology between the rat and human receptors. Orexin-A is equipotent at OX1 and OX2 receptors, while orexin-B displays moderate (~10 fold) selectivity for OX2 receptors.

Independent of the isolation of the orexins, another group identified a hypothalamic-specific mRNA encoding a precursor protein they termed prepro-hypocretin and predicted that proteolytic processing would yield two peptides, hypocretin-1 (residues 28-66) and hypocretin-2 (residues 69-97). These researchers also predicted both peptides would be amidated and added the caveat that the N-terminus of hypocretin-1 was not defined. Subsequent comparisons showed that prepro-orexin and prepro-hypocretin were the same peptide, and that orexin-B and amidated hypocretin-2 were identical. Moreover, orexin-A and hypocretin-1 corresponded, allowing for the overestimation of the N-terminus of hypocretin-1.

Prepro-orexin mRNA is found in the hypothalamus, and to a markedly lesser extent, the testes, adrenals and myenteric plexus. Orexin-A and orexin-B are predominantly located in the hypothalamus, but due to extrahypothalamic projections are also found elsewhere in the brain, most notably the locus coeruleus and spinal cord, as well as in the adrenals and small intestine. OX1 receptors are expressed mainly in the hypothalamus and locus coeruleus, as well as in the hippocampus, dorsal raphe and, to a lesser extent, other brain areas and the spinal cord. OX2 receptors are also expressed in the hypothalamus, as well as the cortex and the spinal cord, and a few discrete brain nuclei. Both receptors are also expressed in the pituitary and the gut.

Several compound tools have been developed to help characterize the orexin system. These include two peptides, [Ala27]orexin-B(6-28) and [Pro11]orexin-B(6-28), both of which show at least 1000-fold selectivity for OX2 versus OX1 receptors. A number of small molecule antagonists for orexin receptors have been reported, notably the OX1 receptor antagonist, SB-334867-A, which displays affinities of 40 and 2000 nM at OX1 and OX2 receptors, respectively. In rats, this compound has been shown to inhibit feeding, to accelerate the transition between feeding and resting, and to have effects on analgesia, hypertension and the central release of norepinephrine. Another non-peptide orexin receptor antagonist, SB-674042, displays a >100 fold selectivity for inhibiting calcium mobilization induced by OX1 versus OX2 receptor activation.

The orexin system has been implicated in the control of feeding behavior, especially the behavioral satiety sequence and energy homeostasis, as well as neurocrine and cardiovascular effects, including modulation of blood pressure. The orexins are also involved in the regulation of the sleep-wake cycle, with orexin-A stimulating the locus coeruleus and so increasing arousal. Several studies have shown that a mutation in the OX2 receptor in some breeds of dog leads to narcolepsy. In addition, disruption of the prepro-peptide in mice or rats gives rise to narcoleptic symptoms, while disruption of OX1 or OX2 receptors in mice also leads to sleep abnormalities. Furthermore, patients with narcolepsy appear to have a disrupted orexin system, with most cases seeming to occur as a result of a lack of orexin.


The Table below contains accepted modulators and additional information.



Currently Accepted Name OX1 OX2
Alternate Name Hcrtr1
Orexin-A receptor
Structural Information 425 aa (human) 445 aa (human)
Subtype Selective Agonists Orexin-A (O6012) > Orexin-B (SPC0204 (h), O6262 (r,m)) Orexin-A (O6012) > Orexin-B (SPC0204 (h), O6262 (r,m))
Subtype Selective Antagonists SB-334867-A
Not Known
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG)
Radioligand of Choice [125I]-Orexin-A
Tissue Expression Prefrontal cortex (r)
Infralimbic cortex (r)
Hippocampus (r)
Paraventricular thalamic nucleus (r)
Ventromedial hypothalamic nucleus (r)
Dorsal raphe nucleus (r)
Locus coeruleus (r)
Adrenal zona fasciculate-reticularis (h)
Adrenal medulla (h)
Cerebral cortex (r)
Basal forebrain cholinergic nuclei (r)
Hippocampus (r)
Paraventricular premammillary nuclei (r)
Midline and intralaminar thalamus (r)
Raphe nuclei (r)
Hypothalamic nuclei (r)
Physiological Function Sleep-wakefulness, energy homeostasis Sleep-wakefulness
Disease Relevance Not known Narcolepsy (canine)



SB-334867-A: 1-(2-Methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl-urea hydrochloride
SB-674042: (5-(2-Fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone)

h: human
m: mouse
r: rat