Orexin receptors as therapeutic drug targets.

Orexin (hypocretin) receptor antagonists stand as a model for the development of targeted CNS small-molecule therapeutics. The identification of mutations in the gene for the orexin 2 receptor responsible for canine narcolepsy, the demonstration of a hypersomnolence phenotype in hypocretin knockout mice and the disruption in orexin signaling in narcoleptic patients provides clear genetic proof of concept for targeting orexin-induced arousal for the treatment of insomnia. The full characterization of the genes encoding orexin and its two cognate receptors enabled the rapid development of in vitro and ex vivo assays with which to identify lead compound structures and to optimize potency and pharmacokinetic properties. Polysomnographic measures with cross-species translatability capable of measuring the sleep-promoting effects of orexin receptor antagonists from mice to man, and the existence of knockout models not only allow efficacy assessment but also the demonstration of mechanism of action. Focused efforts by a number of groups have identified potent compounds of diverse chemical structure with differential orexin receptor selectivity for either the orexin 1 receptor (OX₁R) or the orexin 2 receptor (OX₂R), or both. This work has yielded tool compounds that, along with genetic models, have been used to specifically define the role these receptors in mediating orexin-induced arousal and vigilance state control. Optimized dual receptor antagonists with favorable pharmacokinetic and safety profiles have now demonstrated efficacy in clinical development and represent a distinct mechanism of action for the treatment of insomnia relative to current standard of care.