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The orexins (hypocretins) are a newly discovered family of neuropeptides which play a role in regulating feeding and wakefulness. The family currently consists of two members; orexin A and orexin B (33- and 28-residues respectively), which are produced from a common precursor prepro-orexin (130 amino acids). Cell bodies of orexin-containing neurons are largely confined to the lateral hypothalamus, an area classically linked to feeding stimulation. Intracerebroventricular injections of orexin A and orexin B stimulate feeding in a dose-related manner, with orexin A being significantly more effective than orexin B. Orexins are also strongly linked to the regulation of sleep-activity cycles, which may restrict the use of orexin ligands in the treatment of obesity. The orexins activate two G-protein-coupled receptors (OX1 and OX2) also found predominantly in the hypothalamus. Orexin A is the selective endogenous agonist for OX1 and blocking this receptor modulates food and water intake.
Written by Sonia Tucci, Lynsay Kobelis and Tim Kirkham, this review provides a synopsis of the increasing number of peptides that have been implicated in appetite regulation and energy homeostasis; putative roles of the major peptides are outlined and compounds available from Tocris are listed.
|Receptor Subtype||OX1 Receptors||OX2 Receptors|
|Transduction Mechanism||↑ PLC → ↑ Ca2+ influx||↑ PLC → ↑ Ca2+ influx|
|Primary Locations||Ventromedial hypothalamus, locus coeruleus, median raphe, hippocampus, tenia tecta||Cerebral cortex (layers IV-VI), medial hypothalamus, paraventricular hypothalamus, nucleus accumbens, subthalamic and paraventricular thalamus, anterior pretectal nucleus|
|Likely Physiological Roles||Sleep-wakefulness, energy homeostasis||Sleep-wakefulness|
|Key Compounds||Ki Values (nM)|
|Orexin A (human, rat, mouse) (1455)||20||38|
|Orexin B (human) (1456)||420||36|
|SB 334867 (1960)||7.2*||< 5*|
|SB 408124 (1963)||21.7†||1405†|
|[Ala11,D-Leu15-Orexin B (2142)||52‡||0.13‡|
* pKb value, † Kb value, ‡ EC50 value
Smart et al (1999) Cahracterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell line using FLIPR. Br.J.Pharmacol. 128 1. Sutcliffe and de Lecea (2000) The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. J.Neurosci. Res. 62 161. Smart (1999) Orexins: a new family of neuropeptides. Br.J.Anaesth. 83 695. Smart et al (2001) SB-334867-A: the first selective orexin-1 receptor antagonist. Br.J.Pharmacol. 132 1179. Asahi et al (2003) Development of an Orexin-2 receptor selective agonist [Ala11,D-Leu15orexin -B. Bioorg.Med.Chem.Letts. 13 111. Langmead et al (2004) Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br.J.Pharmacol. 141 340.