The orexin receptors OX1 and OX2 play important roles in the regulation of sleep-wake
cycles, feeding, reward and energy homeostasis. Since these G protein-coupled receptors were deorphanised
in 1998, more than 200 patents containing orexin receptor antagonists have been filed and,
in 2014, suvorexant (Belsomra®) became the first of these compounds to receive approval from the
FDA. Suvorexant is a dual orexin receptor antagonist (DORA) which is available for the treatment of
insomnia. This review provides a historical perspective on the discovery and development of DORAs
as well as selective OX1 receptor antagonists (1-SORAs) and selective OX2 receptor antagonists (2-SORAs). 2-SORAs are under clinical evaluation for their ability to modulate sleep, and 1-SORAs
have shown promise for the treatment of addiction in pre-clinical animal models. Detailed medicinal
chemistry case studies are presented and future opportunities for orexin receptor antagonists are considered.
Keywords: Antagonist, DORA, Insomnia, Orexin, Sleep, SORA, Suvorexant.
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