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The orexin 2 receptor plays a central role in maintaining sleep and wakefulness. Recently, it has been shown that sleep and wakefulness orchestrate the proliferation and differentiation of oligodendrocytes. Here, we explored the role of a selective orexin 2 receptor antagonist (JNJ-10397049) in proliferation and differentiation of neural progenitor cells (NPCs). We evaluated the proliferation potential of NPCs after exposure to different concentrations of JNJ-10397049 by using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide and neurosphere assays. Moreover, the expression of differentiation markers was assessed by immunocytochemistry and real-time polymerase chain reaction. JNJ-10397049 significantly increased the proliferation of NPCs at lower concentrations. In addition, orexin 2 receptor antagonist facilitated progression of differentiation of NPCs towards oligodendroglial lineage by considerable expression of Olig2 and 2\',3\'-cyclic-nucleotide 3\'-phosphodiesterase as well as decreased expression of nestin marker. The results open a new avenue for future investigations in which the production of more oligodendrocytes from NPCs is needed.

The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.

Orexin-A (hypocretin-1) is a neuropeptide that is produced in the lateral hypothalamic area (LHA) and promotes widespread cortical activation. We investigated the effect of SB-334867, a selective orexin receptor 1 (OXR1) antagonist, on phospholipase C-β3 (PLCβ3) level using slices of rat hippocampus preparations and immunohistochemistry. We used three Wistar rats in each of three groups. The control group was untreated rats and SB vehicle and SB groups received SB vehicle and 10 mg/kg SB-334867 daily from postnatal day (PND) 12 to PND30, respectively. We found that the orexin receptor antagonist decreased the PLCβ3 level in the inner and outer blades of dentate gyrus (DG) compared to SB vehicle treated rats. Orexin may increase the PLCβ3 level in most regions of the rat hippocampus.

Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects.
Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52).
ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures.
The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.

The morphinan-type orexin 1 receptor (OX1R) antagonists such as YNT-707 (2) and YNT-1310 (3) show potent and extremely high selective antagonistic activity against OX1R. In the course of our studies of the essential structure of 2, we identified new scaffolds by simplification of the morphinan skeleton. However, the new chemical entities carrying the D-ring removed scaffold showed insufficient activity. To improve the activity of these derivatives, we investigated the effect of substituents mainly focused on the 17-nitrogen group. The 17-N-substituted derivatives, as well as the cyclic derivatives, were synthesized and examined the OX1R antagonistic activity. The assay results showed the interesting relationship between the OX1R antagonistic activity and the substituents on the 17-nitrogen: the antagonistic activity was increased as the bulkiness of 17-substituents increased. Finally, the 17-N-Boc derivative 14a showed the most potent OX1R antagonistic activity (Ki = 14.8 nM).

Alcohol use disorder (AUD) is a complex neuropsychiatric disease state in which currently approved pharmacotherapeutics are of relatively low effect at a population level. One reason for this may be that current pharmacotherapeutics focus on the reward pathway in relapse prevention, rather than addressing AUD from a holistic perspective. Importantly, one often overlooked symptom of AUD is sleep disruption. In recent years, an efficient, relatively low risk and economic strategy that has proven successful in other disorders is the repositioning or repurposing of drugs approved for the treatment of other indications. Suvorexant, a dual orexin receptor antagonist, has been licensed for the treatment of insomnia in the USA, Australia and Japan. The orexin system also plays a role in the emotional dysregulation that occurs during withdrawal from alcohol use and in alcohol-seeking behaviours. These two factors prompted the planning of a clinical trial into the use of suvorexant to treat insomnia in alcohol dependent individuals during and 24 weeks post-acute alcohol withdrawal. In this review we outline the comorbid nature of AUD and sleep disruptions. We then highlight the role of the orexin system in both sleep-wake regulation and AUD. Finally, we discuss our plan for a Phase II double blind placebo controlled trial examining the effectiveness of suvorexant for the treatment of comorbid insomnia and AUD.

Orexins (OXA, OXB) are hypothalamic peptides playing crucial roles in arousal, feeding, social and reward-related behaviours. A recent study on juvenile rats suggested their involvement in vision modulation due to their direct action on dorsal lateral geniculate (dLGN) neurons. The present study aimed to verify whether a similar action of OXA can be observed in adulthood. Thus, in vivo and in vitro electrophysiological recordings on adult Wistar rats across light-dark and cortical cycles were conducted under urethane anaesthesia. OXA influenced ~28% of dLGN neurons recorded in vivo by either excitation or suppression of neuronal firing. OXA-responsive neurons did not show any spatial distribution nor represent a coherent group of dLGN cells, and responded to OXA similarly across the light-dark cycle. Interestingly, some OXA-responsive neurons worked in a cortical state-dependent manner, especially during the dark phase, and \'preferred\' cortical activation over slow-wave activity induced by urethane. The corresponding patch clamp study confirmed these results by showing that < 20% of dLGN neurons were excited by OXA under both light regimes. The results suggest that OXA is involved in the development of the visual system rather than in visual processes and further implicate OXA in the mediation of circadian and arousal-related activity.

The ventral tegmental area (VTA) is a key brain region, involved in the dependency on nicotine. Studies have shown that orexin and cannabinoids are likely to play an important role in nicotine dependency. In this study, the effect of orexin receptor-2 (OX2R) and cannabinoid receptor-1 (CB1R) blockade were investigated in response to nicotine in male rats, on the neural activity of VTA. Nicotine was injected subcutaneously and its effect on the firing of VTA non-dopaminergic (ND) neurons was investigated, using in vivo extracellular single unit recording. Nicotine increased the ND neuronal activity of the VTA. AM251 (0.18, 0.9, 1.8 nmol/0.3 µL), as a selective cannabinoid CB1R antagonist, and TCS-OX2-29 (0.5, 1, 5 nmol/0.3 µL), as a selective OX2R antagonist, individually or simultaneously were microinjected into the VTA. The results revealed that blockade of OX2R and CB1R in the VTA could prevent the increased firing rate, caused by nicotine. Concurrent administration of TCS-OX2-29 and AM251 could decrease responsiveness of VTA-ND neurons to nicotine, but it did not show a greater response than their single application. Because the synergistic effect was not observed in the simultaneous blockade of these two receptors, therefore, in order to detect the interactions of these two receptors, further studies are needed in the field of intracellular signaling.

We assess the stability of two previously suggested binding modes for the neuropeptide orexin-A in the OX2 receptor through extensive molecular dynamics simulations. As the activation determinants of the receptor remain unknown, we simulated an unliganded receptor and two small-molecular ligands, the antagonist suvorexant and the agonist Nag26 for comparison. Each system was simulated in pure POPC membrane as well as in the 25% cholesterol-POPC membrane. In total, we carried out 36 μs of simulations. Through this set of simulations, we report a stable binding mode for the C-terminus of orexin-A. In addition, we suggest interactions that would promote orexin receptor activation, as well as others that would stabilize the inactive state.