Editorial [Hot Topic: Recent Advances in Medicinal Chemistry for Treatment of Sleep and Wake Disorders (Guest Editor: James Barrow) ]

As one of the most obvious and fundamental processes in biology, sleep has attracted a great deal of attention from ancient philosophers to present-day biomedical researchers. Given its importance to normal daily functioning, research into medicinal agents that affect sleep and wakefulness has progressed beyond the empirical exploration of herbal preparations practiced for millennia. When chemists gained the ability to routinely prepare and test discrete, pure substances in the 19th century, the first generation of sedative and wake-promoting agents were identified based on crude, binary in vivo sleep/wake readouts. Advances in neuroscience and molecular pharmacology have identified the targets of the first-generation agents and provided insight into strategies for more selective and safer methods of modulating these pathways. These advances have also given medicinal chemists new targets such as the orexin system, and advances in EEG recording and interpretation allow more thorough evaluation of overall sleep architecture. This issue of Current Topics in Medicinal Chemistry focuses on several exciting topics in the area of compounds for sleep and wake disorders. John Renger starts off with a comprehensive overview of the neuroscience behind sleep and wake regulation as well as the localization and role of the important neurotransmitters such as GABA, histamine, serotonin, melatonin, orexin, and others. Following are individual reviews on the recent progress in areas of sleep/wake agents where there has been active medicinal chemistry interest. Missing from this compilation are areas such as selective histamine H1 antagonists which are known to have powerful sedative effects; however, most medicinal chemistry is focused on non-brain penetrant compounds for allergy and therefore outside the scope of this issue. In focusing on target-based medicinal chemistry, agents with poorly defined mechanisms were also omitted, such as the important wake-promoter modafinil. Many important neurotransmitter systems are under active investigation. Melatonin is an important signaling hormone that modulates sleep and circadian patterns, and Silvia Rivara, Marco Mor, Annalida Bedini, Gilberto Spadoni, and Giorgio Tarzia describe the medicinal chemistry around this target that has recently provided ramelteon (Rozerem) for clinical use. Serotonin acts through numerous receptors in the CNS, and recent research has demonstrated that selective antagonism of the 5HT2A subtype can have clinically important effects on sleep architecture. Bradley Teegarden, Hussien Al Shamma, and Yifeng Xiong review this area with focus on the many compounds currently in clinical development. One of the best examples of how fast neuroscience drug discovery is progressing is described in A.J. Roecker and Paul Coleman's review of orexin antagonists. In less than 10 years from identification of the role of the orexin system, almorexant achieved clinical proof of concept in insomnia and is currently in Phase 3 trials. The search for safe and effective wake-promoting agents has been a challenging objective. Recent discoveries in the histamine signaling system have revealed that subtype selective histamine H3 antagonists/inverse agonists may have advantages over classical wake-promoters such as amphetamine, modafinil, and caffeine. The review by Emily Stocking and Michael Letavic summarize a very active area of research as histamine H3 antagonists may have therapeutic indications beyond just treating excessive daytime sleepiness. Given the medical need for safe and effective sleep and wake promoting agents, there remains intense research in this area. Fine-tuning of established mechanisms as well as discovery and development of new targets continues in the search for improved daytime functioning. This issue provides a glimpse into the activity around some of the most promising avenues, and many thanks go out to the authors for their timely and comprehensive reviews.