Abstract
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.