Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia.

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Roch C, Bergamini G, Steiner MA, Clozel M

Nonclinical pharmacology of daridorexant: a new dual orexin receptor antagonist for the treatment of insomnia.

Psychopharmacology (Berl). 2021 Oct;238(10):2693-2708. doi: 10.1007/s00213-021-05954-0. Epub 2021 Aug 20.

PubMed ID

34415378 [ View in PubMed

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Abstract

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. 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. 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. By specific binding to both orexin receptors, daridorexant inhibits the actions of the wake-promoting orexin (also called hypocretin) neuropeptides. This mechanism avoids a more widespread inhibition of neuronal pathways and associated side effects that are intrinsic to positive allosteric GABA-A receptor modulators. Here, we review the general pharmacology of daridorexant, based on nonclinical pharmacology studies of daridorexant, unpublished or already described, or based on work with other DORAs. 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.

DrugBank Data that Cites this Article

Drugs

Daridorexant

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Daridorexant	Orexin receptor type 1	Protein	Humans	Yes	Antagonist	Details
Daridorexant	Orexin receptor type 2	Protein	Humans	Yes	Antagonist	Details