Insomnia persistently affects the quality and quantity of sleep. Currently approved treatments for
insomnia primarily target γ-
aminobutyric acid-A (
GABA-A) receptor signalling and include
benzodiazepines and
GABA-A receptor modulators. These drugs are used to address this
sleep disorder, but have the potential for side effects such as tolerance and dependence, making them less attractive as maintenance
therapy. Forward and reverse genetic approaches in animals have implicated
orexin signalling (also referred to as
hypocretin signalling) in the control of vigilance and sleep/wake states. Screening for
orexin receptor antagonists using in vitro and in vivo methods in animals has identified compounds that block one or other of the
orexin receptors (single or
dual orexin receptor antagonists [SORAs and DORAs], respectively) in animals and humans. SORAs have primarily been used as probes to further elucidate the roles of the individual
orexin receptors, while a number of DORAs have progressed to clinical development as
pharmaceutical candidates for
insomnia. The DORA
almorexant demonstrated significant improvements in a number of clinically relevant sleep parameters in animal models and in patients with
insomnia but its development was halted.
SB-649868 and
suvorexant have demonstrated efficacy and tolerability in Phase II and III trials respectively. Furthermore,
suvorexant is currently under review by the Food and Drug Administration for the treatment of
insomnia. Based on the publication of recent non-clinical and clinical data,
orexin receptor antagonists potentially represent a targeted, effective and well-tolerated new class of medications for
insomnia.