The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold

Abstract

BackgroundDrugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound’s mechanism of action.ResultsDual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX2R) occupancies in the range of 65 to 80%. In rats, the time course of OX2R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes.ConclusionThe higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.

Orexin 2 Receptor Antagonism is Sufficient to Promote NREM and REM Sleep from Mouse to Man

“…Circadian oscillations in orexin peptides A and B within cerebrospinal fluid correlate with arousal cycles12, and exogenous administration of the neuropeptides is sufficient to drive wakefulness in rodents, particularly during the inactive phase34. A lack of orexin signaling is associated with narcolepsy, a disorder characterized by uncontrollable sleep episodes and hypersomnolence5.…”

Hypothalamic orexin’s role in exacerbated cutaneous vasodilation responses to an anxiogenic stimulus in a surgical menopause model

“…This compound is a close structural analog of suvorexant, and the 30 mg/kg p.o. dose of DORA-12 being used here achieves a plasma Cmax of 2.02 μM with CSF exposure of 66 nM and ex vivo occupancy of 97%, and has been shown to promote sleep in rats (Gotter et al, 2013). …”

Safety Pharmacology Investigations on the Nervous System: An Industry Survey

“…Authier et al 2015JPTM 6/2/2016 A wide range of approved drugs are associated with drug induced sleep disturbances such as insomnia, including beta-blockers (Chang et al, 2013;Moser, 1979), corticosteroids (Ciriaco et al, 2013), selective serotonin-reuptake inhibitors (SSRI) (Asnis, et al, 1999) or acetylcholinesterase inhibitors (Cooke et al, 2006). Polysomnography is a well-established technique for sleep disturbance assessment and is well established in laboratory animal species commonly used for non-clinical drug SP testing including rodents (Gotter et al, 2013), dogs and non-human primates (Authier et al, 2014).…”