In 2007, our group showed for the first time that a dual orexin receptor antagonist (DORA) of the orexin type 1 and 2 receptors (OX1R, OX2R), namely almorexant, promoted sleep in rats, dogs, and healthy subjects (Brisbare-Roch et al. In recent years, the orexin (also called hypocretin) system has been discovered as a target for the development of a new class of sleep medication.

2011 Gunja 2013 Möhler 2006 Vermeeren 2004 Wafford and Ebert 2008 Wang et al. Despite their effectiveness, these medications can elicit a number of side effects, such as next-morning residual sleepiness, motor incoordination, falls, memory and cognitive impairment, and the potential of abuse, dependence, and tolerance, limiting their use (Dolder and Nelson 2008 Frey et al. Z-drugs (zopiclone, zolpidem, zaleplon), which are positive allosteric GABA-A subunit alpha 1 receptor modulators and the most widely used hypnotics, drive sleep by causing a broad inhibition of central nervous system (CNS) activity (Atkin et al. Treatments for insomnia target gamma-aminobutyric acid type-A (GABA-A), serotonin, histamine, or melatonin receptors. Insomnia is associated with long-term consequences including hypertension, diabetes, and depression (Institute of Medicine (US) Committee on Sleep Medicine and Research 2006 Kyle et al. Daytime tiredness, distress, altered mood, and memory can significantly impair social, occupational, educational, academic, or behavioral aspects of life (Carey et al. Daytime impairment can negatively influence an individual’s quality of life in different manners. Insomnia, characterized by difficulties with sleep onset and/or sleep maintenance and impairment of daytime functioning (American Academy of Sleep Medicine 2014), chronically affects approximately 5–20% of the adult population (Roth et al. Some unique features of daridorexant will be highlighted, such as the promotion of natural and surmountable sleep, the preservation of memory and cognition, the absence of tolerance development or risk of physical dependence, and how it can benefit daytime functioning.

Here, we review the general pharmacology of daridorexant, based on nonclinical pharmacology studies of daridorexant, unpublished or already described, or based on work with other DORAs. This mechanism avoids a more widespread inhibition of neuronal pathways and associated side effects that are intrinsic to positive allosteric GABA-A receptor modulators. By specific binding to both orexin receptors, daridorexant inhibits the actions of the wake-promoting orexin (also called hypocretin) neuropeptides. Daridorexant was discovered through a tailored research program aimed at identifying an optimized sleep-promoting molecule with pharmacokinetic properties appropriate for covering the whole night while avoiding next-morning residual activity at efficacious doses. Daridorexant is a new DORA that exhibited in phase 3 trials in insomnia not only a beneficial effect on sleep variables, measured objectively and assessed subjectively, but also an improvement in daytime functioning. Dual orexin receptor antagonists (DORAs) represent a novel type of sleep medication that provide an alternative to the traditionally used positive allosteric gamma-aminobutyric acid (GABA)-A receptor modulators.

Memory note for pharmacology