Research Highlights Hoever, P.; de Haas, S.; Winkler, J.; Schoemaker, R.C.; Chiossi, E.; van Gerven, J.; Dingemanse, J. Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clin Pharmacol Ther, 2010, 87, 593-600. Targeting the Orexin System: A New Approach for Treating Insomnia Sleep is an essential part of our everyday lives that matters more than most people realize. Regulation of the sleep-waking cycle is complex, involving multiple neurological circuits and diverse endogenous molecules. Interplay among assorted neuroanatomical and neurochemical systems maintain the waking state. Sleep-onset is governed by the interacting forces of the sleep drive, which steadily increases with duration of waking and circadian fluctuations. Epidemiological and clinical studies have established that sleep disorders are common and often untreated. Insomnia, one of the most common sleep disorders among adults, is a symptom of difficulty initiating sleep, maintaining sleep, or non-restorative sleep associated with impaired next-day functioning and an increased risk for accidents. Insomnia treatment continues to be dominated by benzodiazepines and related compounds, which are powerful sedatives that enhance the inhibitory action of GABA (γ-aminobutyric acid) in the brain. The hypocretins/orexins are recently-discovered peptides with a discrete localization in the lateral hypothalamus. A single gene encodes hypocretin, which is cleaved by proteolytic processing into two smaller peptides: hypocretin-1 (orexin A) and hypocretin-2 (orexin B). These neurons project throughout the entire brain and spinal cord, providing especially heavy innervation to forebrain and brainstem neuronal populations implicated in wakefulness. Hypocretin/orexin has been implicated in narcolepsy, a human sleep disorder. Two orexin receptor subtypes, OX1R and OX2R, have been cloned. They are serpentine G-protein coupled receptors that bind both orexins with low selectivity and are coupled functionally to Ca++ mobilization, probably through transient receptor potential channels. The hypocretin/orexin system plays an important role in the regulation of sleep and wakefulness, especially in the maintenance of long, consolidated awake periods. Increased hypocretin/orexin activity has been observed during waking and at the end of sleep. Almorexant, a tetrahydroisoquinoline derivative, is a reversible, selective, orally active non-selective OX1 and OX2 receptor antagonist that inhibits functional consequences of OX1 and OX2 receptor activation, such as intracellular Ca++ mobilization. Almorexant promotes sleep in a dose-dependent manner in both healthy volunteers and in patients with primary insomnia. In a new single-dose study, Almorexant was administered in an ascending single-dose (1-1,000 mg) to evaluate tolerability, pharmacokinetics, and pharmacodynamics. In this study, subjects showed no decrements on motor function or reactive time on the following day. No evidence of cataplexy or abnormal REM behavior was reported. However, new studies involving night-time administration in relation of Almorexan in patients with sleep disorders are necessary to explore the role of the hypocretin/orexin during the circadian cycle. Modulation of the sleep-wake cycle is very much a question of timing of dosing, so the development of dosage at the optimal time will be essential for this approach. On the other hand, most of the published compounds targeting the hypocretin/orexin system have been developed using radioliganddisplacement assays or simple functional assays (intracellular Ca++ release) in recombinant cells. Hypocretin/orexin signaling cascades operating in the central nervous system will allow the development of more specific assays and generate compounds to block or activate defined branches of the signaling cascades (e.g. MAP kinase cascades), potentially creating drugs with different efficacy profiles.