Surrey Sleep Research Centre, University of Surrey, Guildford, Surrey, GU2 7XP, UK.
Surrey Clinical Trials Unit, University of Surrey, Guildford, Surrey, GU2 7XP, UK.
Neuropsychopharmacology. 2022 Feb;47(3):719-727. doi: 10.1038/s41386-021-01175-3. Epub 2021 Oct 9.
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.
食欲肽的作用多种多样，由食欲肽-1 和食欲肽-2 受体介导。已证明靶向这两种受体的拮抗剂可促进睡眠的启动和维持。在这里，我们使用两种剂量（20 和 50mg）高度选择性的食欲肽-2 受体拮抗剂（2-SORA）（JNJ-48816274），在一项随机、双盲、安慰剂对照、三周期交叉临床试验中研究了食欲肽-2 受体在睡眠调节中的作用。我们使用了睡眠中断的相位提前模型，其中睡眠的开始被安排在昼夜觉醒维持区域。我们评估了 18 名没有睡眠障碍的健康男性参与者的客观和主观睡眠参数、药代动力学特征以及对认知表现的残留影响。单独的相位提前模型（安慰剂条件）导致与基线睡眠相比（在习惯时间安排），睡眠期开始时的睡眠中断。与安慰剂相比，JNJ-48816274 的两种剂量均显著增加了总睡眠时间、快速眼动睡眠时间和睡眠效率，减少了潜伏期至持续睡眠、入睡潜伏期和快速眼动潜伏期。NREM 和 REM 睡眠的整夜 EEG 谱密度均不受任何剂量的影响。与安慰剂相比，参与者报告在服用 JNJ-48816274 后睡眠质量明显改善，醒来时感觉更清爽。没有观察到对客观表现测量的明显残留影响，并且该化合物耐受性良好。总之，选择性食欲肽-2 受体拮抗剂 JNJ-48816274 在昼夜节律周期中更早地安排睡眠时可迅速诱导睡眠，并改善自我报告的睡眠质量，而不会影响清醒时的表现。
