Orexin Receptor Antagonists Differ from Standard Sleep Drugs by Promoting Sleep at Doses That Do Not Disrupt Cognition

Selective orexin receptor antagonism promotes sleep at doses lower than those that impair attention and memory in contrast to the GABA receptor–positive allosteric modulators currently in use. Sleep Without the After Effects Currently available treatments for insomnia can produce a number of central nervous system–based cognitive side effects, including the potential to impair memory and attention. Recently, selective dual orexin receptor antagonists, such as suvorexant and almorexant, have been shown to promote sleep onset and maintenance in clinical trials for patients with insomnia. In new work, Uslaner and colleagues compared sleep-promoting doses to the cognitive-impairing doses for an orexin receptor antagonist, DORA-22, versus sleep drugs currently in use: zolpidem, diazepam, or eszopiclone. At doses that produced equivalent amounts of sleep in rat and rhesus monkey, zolpidem, diazepam, and eszopiclone significantly disrupted attention and memory, whereas DORA-22 promoted sleep at doses that did not exert measurable effects on cognition. Furthermore, when compared to the other insomnia treatments that modulate γ-aminobutyric acid (GABA) receptor function, the authors saw greater separation for orexin receptor antagonism between doses that promoted sleep and doses that reduced expression of a hippocampal gene involved in synaptic plasticity called Arc. These findings suggest that dual orexin receptor antagonists might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently available. Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABAA)–positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound’s minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity–regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently in use.