CHAPTER 16: Recent Chronology of Orexin Pharmacology and Its Potential as a Treatment for Primary Insomnia

An understanding of the function of orexin peptides and their cognate receptors offers new insights into the role of hypothalamic control of sleep and wake, along with revealing previously undefined connections between feeding, reward and addiction. Despite being relatively recently discovered, progress in this field has been rapid. In just over 14 years, this area has moved from the identification of the orexin (hypocretin) peptide to the development of late-stage clinical drug candidates targeting the orexin receptors for insomnia. The swift pace of discovery was ignited by the identification of the link between orexin signalling and human narcolepsy, and accelerated with the development of solid genetic animal models and focused research efforts by academic and industrial investigators resulting in unprecedented translational pharmacology. The recent demonstration of clinical efficacy with dual orexin receptor antagonists for the treatment of insomnia has invigorated the sleep research field with a new genetically based mechanism of action for sleep therapeutics, and has provided direction to build on these findings. This chapter describes the discovery and characterization of the orexin neurotransmitter system, the impact of translational genetic models and behavioural monitoring and the development of novel small-molecule orexin receptor antagonists for insomnia, reviews recent clinical experience and discusses the emerging opportunities for targeting orexin signalling in other neurological and psychiatric diseases.