Research ArticleDrug Discovery

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

Science Translational Medicine  03 Apr 2013:
Vol. 5, Issue 179, pp. 179ra44
DOI: 10.1126/scitranslmed.3005213

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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.