Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray cryst...

Abstract Introduction The orexin neuropeptide–receptor system is a central sleep and wake regulator in the brain. two receptor subtypes, OX1R OX2R, are expressed either alone or together all major wake-promoting brain areas. OX2R activation by orexins causes elevation of intracellular calcium, which enhances synaptic transmission secondary, monoaminergic wake- arousal-promoting neurotransmitter...

Orexins (hypocretins) are recently discovered excitatory transmitters implicated in arousal and sleep. Yet, their ionic and signal transduction mechanisms have not been fully clarified. Here we show that orexins suppress G-protein-coupled inward rectifier (GIRK) channel activity, and this suppression is likely to lead to neuronal excitation. Cultured neurons from the locus coeruleus (LC) and th...

introduction: orexin-a and b (hypocretin 1 and 2) are neuropeptides that are mostly expressed in the posterior and lateral hypothalamus (lh). intracisternal (icv) and intratechal (it) injections of orexin-a (hypocretin-1) have been shown to elicit analgesic responses in formalin test. however, the locations of central sites that may mediate these effects have not been clearly elucidated. orexin...

Orexins (hypocretins) are recently discovered excitatory transmitters implicated in arousal and sleep. Yet, their ionic and signal transduction mechanisms have not been fully clarified. Here we show that orexins suppress GIRK channel activity, and this suppression is likely to lead to neuronal excitation. Cultured neurons from the locus coeruleus (LC) and the nucleus tuberomammillaris (TM) were...

MicroRNAs (miRNAs) are short, 22–25 nucleotide long transcripts that may suppress entire signaling pathways by interacting with the 3’-untranslated region (3’-UTR) of coding mRNA targets, interrupting translation and inducing degradation of these targets. The long 3’-UTRs of brain transcripts compared to other tissues predict important roles for brain miRNAs. Supporting this notion, we found th...

Orexins (hypocretins) are novel neuropeptides that appear to play a role in the regulation of energy balances. Orexin-A (OXA) increases food intake in rodents, and fasting activates OXA neurons in both the lateral hypothalamic area and gut. OXA is also found in the endocrine pancreas; however, little is known about its release or functional significance. In this study, we show that depolarizing...

The orexin/hypocretin neuropeptides are produced by a cluster of neurons within the lateral posterior hypothalamus and participate in neuronal regulation by activating their receptors (OX1 and OX2 receptors). The orexin system projects widely through the brain and functions as an interface between multiple regulatory systems including wakefulness, energy balance, stress, reward, and emotion. Re...

Recent studies have established that the orexin system is a critical regulator of sleep/wake states. Deficiency of orexin signaling results in the sleep disorder narcolepsy-cataplexy in humans, dogs, and rodents. These findings have brought about the possibility of novel therapies for sleep disorders including narcolepsy-cataplexy. Furthermore, accumulating evidence has indicated that the orexi...