IJMS, Vol. 26, Pages 8700: Targeting the Orexin System in the Pharmacological Management of Insomnia and Other Diseases: Suvorexant, Lemborexant, Daridorexant, and Novel Experimental Agents

International Journal of Molecular Sciences doi: 10.3390/ijms26178700

Authors:
Kacper Żełabowski
Wiktor Petrov
Kacper Wojtysiak
Zuzanna Ratka
Kamil Biedka
Michał Wesołowski
Katarzyna Fus
Dawid Ślebioda
Malwina Rusinek
Maria Sterkowicz
Izabela Radzka
Agnieszka Chłopaś-Konowałek

The orexin (hypocretin) system plays a central role in regulating the sleep–wake cycle through two neuropeptides, orexin-A and orexin-B, which act on OX1R and OX2R receptors. Emerging evidence links heightened orexin signaling with the pathophysiology of chronic insomnia. This review outlines the neurobiology of the orexinergic system, compares the pharmacological profile of dual orexin receptor antagonists (DORAs) to traditional GABAergic hypnotics, and evaluates the clinical efficacy and safety of Suvorexant, Lemborexant, and Daridorexant. DORAs function by selectively dampening orexin-driven arousal, thereby facilitating sleep onset and maintenance without disrupting natural sleep architecture. Clinical trials have shown that these agents significantly reduce sleep latency and enhance sleep continuity, with a favorable side effect profile. Overall, DORAs represent a distinct and clinically advantageous option for insomnia treatment, with growing interest in their potential utility across mood, anxiety, and neurodegenerative disorders.

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Kacper Żełabowski www.mdpi.com