0103 REM SLEEP IS INDUCED BY DUAL AND OREXIN 2 RECEPTOR ANTAGONISTS VIA MECHANISMS BEYOND ALPHA1-NORADRENERGIC SIGNALING

Orexin receptor (OX1R, OX2R) antagonism induces sleep architecture characterized by increases in both NREM and REM reminiscent of unmedicated sleep. REM sleep is thought to be controlled in part by noradrenergic neurons of the locus coeruleus (LC), a site of selective OX1R expression. This work utilizes selective DORA and 2-SORA antagonists in combination with prazosin (alpha1-noradrenergic blocker) in genetic models to determine specific roles of OX1R and OX2R in sleep architecture changes induced by DORAs and 2-SORAs. Sleep architecture was evaluated by polysomnography in preclinical animals (mice, rats, dogs, and rhesus monkeys) via radio-telemetry implants in across 3–5 days of drug administration. Stages of sleep were quantified with automated software modules evaluating ECoG, EMG, EOG (dog, monkey) data. Drug-induced sleep stage changes were correlated with receptor occupancy in transgenic rats expressing hOX2R at Cmax. A double-blind, randomized, 4-period crossover Phase I polysomnography study evaluated responses to single doses of 2-SORA, MK-1064, in twenty healthy male subjects. In rats, NREM and REM sleep induced by DORAs is statistically no different from un-medicated inactive phase sleep. Mouse genetic models indicate that OX2R primarily modulates orexin-induced arousal, while OX1R appears involved in vigilance state gating. Prazosin similarly augmented REM sleep induced by DORAs and 2-SORAs, however, indicating that noradrenergic signaling from the LC is not maximally inhibited by either treatment. In rats, sleep was induced by lower receptor occupancies of DORAs relative to 2-SORAs. Across mammals including humans, REM sleep was induced by MK-1064, a 2-SORA exhibiting 3000x binding selectivity for OX2R over OX1R. DORAs promote sleep by attenuating arousal and reducing sleep stage threshold through mechanisms beyond alpha1-noradrenergic signaling of the LC. 2-SORAs promote REM sleep across mammals in a manner similar to DORAs and do not appear to measurably differentiate from DORAs in sleep architecture. This work was funded by Merck & Co., Inc.