Orexin receptor

The diffuse nature of orexinergic projections is consistent with combined patterns of expression of the two orexin receptors, which is widespread but differential and often complementary within and even outside the CNS. OX2Rs are found primarily in structures attributed to control of sleq)-wake functions, whereas OXIRs are more abundant in limbic structures controlling aspects of feeding, autonomic outflow, energy homeostasis, and to a lesser extent also REM-sleq). 

Extrahypothalamic OX-B-like immunoreactivity, reminiscent to that of CRF, has been described in clustered GABAergic neuronal populations, in the lateral division of central nucleus ofthe amygdala, the bednucleus of the stria terminalis, and in the hippocampus. Moreover, ectopic expression of preproorexin mRNA in the gut, ependymal cells, neuroblastomas, and of orexin receptors in adrenal gland, cancer and hematopietic stem cells suggests yet unexplored roles of orexins as paracrine factors controlling blood-brain barrier, and tumor or stem cell function. 

Other names Orexin receptor type 1 Orexin receptor type 2... 

Sakurai, T., Amemiya, A, Ishii, M. el al. (1998). Orexins and orexin receptors a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573-85. 

Distribution of orexin receptor mRNA in the rat brain. FEES Lett. 438, 71-5. 

Bernard, R., Lydic, R. Baghdoyan, H. A. (2006). Hypocretin (orexin) receptor subtypes differentially enhance acetylcholine release and activate G protein subtypes in rat pontine reticular formation./. Pharmacol. Exp. Ther. 317, 163-71. 

Backberg, M., Hervieu, G., Wilson, S. Meister, B. (2002). Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus focus on orexin targets involved in control of food and water intake. Eur. J. Neurosci. 

Vigilance state characterization of orexin- and orexin receptor-deficient rodents... 

Orexin receptor type 1 gene knockout (OXiR-/-)... 

Orexin receptor type 2 gene knockout (OX2K / )... 

Significantly, orexin/ataxin-3 mice respond to intracerebroventricular injection of orexin-A with increased wakefulness and suppression of REM sleep and cataplexy. This pharmacological reversal indicated that orexin receptors remain functional in the absence of orexin neurons, and that these narcoleptic mice can respond to orexin agonists, a finding with significant therapeutic implications (Mieda et al., 2004b). 

The orexin receptor null mice OXjRW, OX2R, and OXjR J ox2R G... 

In finalizing this series of studies, the double receptor knockout mouse (OX,k / ()X2k ) was shown to be phenotypically indistinguishable from orexin mice (Kisanuki et al, 2001), a result that makes the existence of additional orexin receptors unlikely. 

Karteris, E., Machado, R. J., Chen, J. et al. (2005). Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex. Am. J. Physiol. Endocrinol Metab. 288, E1089-100. 

Marcus, J. N. Elmquist, J. K. (2006). Orexin projections and localization of orexin receptors. In The Orexin/Hypocretin System Physiology and Pathophysiology, ed. S. Nishino T. Sakurai, Totowa, NJ Humana Press, pp. 21-43. 

Mieda, M. Yanagisawa, M. (2002). Sleep, feeding, and neuropeptides roles of orexins and orexin receptors. Curr. Opin. Neurobiol. 12, 339-45. 

Willie, J. T., Chemelli, R. M., Sinton, C. M. et at (2003). Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron, 38, 715-30. 

ACT-078573 (20) is the first oral orexin receptor antagonist that penetrates the blood-brain barrier and is capable of inducing a transient and reversible blockade of the two receptors, 0X1 and 0X2 [61]. In animal models, the administration of 20 resulted in a dose-dependent decrease in alertness and increased non-REM and REM sleep. The compound, administered at oral doses ranging from 10 to 300 mg/kg, dose-dependently decreased alertness in rats and exhibited increased duration of REM and non-REM sleep, indicating no intrusive REM sleep that is characteristic of narcolepsy. In dogs, treatment with 20 (10-100 mg/kg p.o.) resulted in dose-dependent reductions in mobility and also induced signs of clinical somnolence. 

Quinolinyl compounds were first reported by Chan et al. as potent orexin receptor antagonists with excellent selectivity for OX1, good brain permeability and in vivo activity following i.p. dosing [62,63]. In fact, compounds SB-334867 (21), SB-408124 (22) and SB-410220 (23) displayed high affinity for the OX1 receptor in both whole cell (Ki — 99, 57 and 19nM, respectively) and membrane formats (X = 38, 27 and 4.5 nM, respectively). Meanwhile, native orexin peptides A and B display affinities for the OX1 receptor with K values of 318 and 1516 nM, respectively. In addition, calcium mobilization studies showed that all three are functional antagonists of the OX1 receptor, with potencies in line with their affinities, and with 50-fold... 

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