Current Topics in Medicinal Chemistry - Volume 8, Issue 11, 2008

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.

The fundamental purpose of sleep remains one of the most compelling questions yet to be answered in the area of neuroscience, if not all of biology. A pervasive behavior among members of the animal kingdom, the functional necessity of engaging regularly in sleep is best demonstrated by showing that failing to do so leads to a broad repertoire of pathological outcomes including cognitive, immunological, hormonal, and metabolic outcomes, among others. Indeed, an absolute requirement for sleep has been shown in studies that have demonstrated that continuous total deprivation of sleep for as short a period as 15 days is generally lethal in some species. The most common clinical sleep disorder, insomnia, is both a principal disease (primary insomnia) as well as a co-morbidity of a large number of other ostensibly unrelated diseases including chronic pain, attention deficit hyperactivity disorder, and depression. From a treatment perspective, restoring normal healthy sleep delivers subsequent benefits in waking cognitive function and mood with the potential for beneficial therapeutic impact on daily functioning across multiple diseases for which restorative healthy sleep is compromised. Our remarkable escalation in understanding the anatomy and physiology of sleep/wake control mechanisms provides new opportunities to modify the neurobiology of sleep and wake-related behaviors in novel and exciting ways. In parallel, expansion of sleep research into novel interfaces between sleep-wake biology and disease states is revealing additional extensive implications of lost sleep. Current investigational and conventional pharmacological approaches for the treatment of sleep and wake disorders are discussed based on their mechanism of action within the CNS and their effect on sleep and wake. This review of recent sleep biology and sleep pharmacology peers into the future of sleep therapeutics to highlight both mechanistic safety and functional outcomes as key for differentiating and establishing success for the next generation of arousal modifying therapeutics.

Melatonin (N-acetyl-5-methoxytryptamine) is synthesized and released by the pineal gland following a circadian rhythm characterized by high levels during the night. It shows several pharmacological effects on diverse cellular and animal models, mainly related to either its antioxidant activity or to its ability to activate specific receptors (MTr). Melatonin is widely used as a self-administered food additive, but its therapeutic potential needs more investigation and is hampered by its poor pharmacokinetics. This review will focus on the medicinal chemistry of agonist ligands of the two human GPCRs MT1 and MT2 melatonin receptors. The recent introduction of ramelteon, a non-selective MT1/MT2 agonist for the treatment of insomnia, and the advancement to clinical trials of other MTr agonists have renewed interest for different classes of compounds endowed with this activity. Several chemical classes of MTr agonists are described in the literature, generally characterized by an indole, or an indole bioisostere, carrying an amide side chain and a methoxy group, or substituents with similar stereoelectronic features. Abundant information is available for nonselective MT1/MT2 ligands, and several molecular models, both ligand- and receptor-based, have been proposed to rationalize their structure activity relationships. Fewer classes of selective agonists have been reported in the literature, and they could help clarifying the physiological role of the two receptor subtypes. A brief discussion on the therapeutic potential of this class of compounds is based on the clinical data available for the agonists ramelteon, agomelatine, β- methyl-6-chloromelatonin (TIK-301) and VEC-162.

Nearly one half of the adult population in the U.S. experience some symptoms of insomnia (difficulties with getting to sleep, maintaining sleep, and/or sleep quality) on a weekly basis. Although most people with insomnia complain primarily of issues related to sleep maintenance and quality, current therapeutic approaches, including GABAA agonists, off label antidepressant use, H1 antagonists and melatonin agonists, primarily address sleep onset latency. The overall sleep architecture, especially that of the deeper stages of NREM sleep known as slow wave sleep (SWS), plays a crucial role in restorative, restful sleep. Through the 5-HT2A receptor, serotonin plays an active role in the regulation of sleep architecture. Antagonists / inverse-agonists of 5-HT2A, such as APD125, volinanserin, eplivanserin, pruvanserin and pimavanserin, are currently being investigated as therapeutics that could improve the treatment of sleep maintenance and quality in people with insomnia.

Actelion Pharmaceuticals achieved clinical proof-of-concept for the treatment of insomnia in 2007 with the release of Phase II data on Almorexant, a potent dual (OX1R/OX2R) orexin receptor antagonist. GlaxoSmithKline also released clinical efficacy data on an orexin receptor antagonist in 2007 for the treatment of insomnia. With these exciting findings, the search for orexin (or hypocretin) receptor antagonists for the treatment of sleep and neurological disorders has recently increased in intensity in the pharmaceutical industry. This review will focus on the medicinal chemistry of orexin antagonists and the potential therapeutic value of this therapy for the treatment of insomnia. Receptor subtype selectivity will also be described to highlight the tools currently available to delineate receptor-specific pharmacology.

The histamine H3 receptor is a pre-synaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. As such, modulation of the histamine H3 receptor is expected to affect wake via control of the release of histamine and to affect cognition via regulation of several other neurotransmitters including acetylcholine and norepinephrine. Over the last several years numerous pre-clinical studies have shown that histamine H3 antagonists promote wakefulness, improve cognition, and in some cases affect food intake. Based on the interest level generated from these early pharmacology studies, and following the cloning and expression of the human histamine H3 receptor, many pharmaceutical companies began drug discovery programs aimed at the identification of histamine H3 antagonists suitable for human clinical trials. These efforts have led to many new chemotypes, and several promising compounds have recently entered the clinic for a variety of conditions, including ADHD, Narcolepsy, EDS associated with Narcolepsy, Cognitive disorders and Schizophrenia. Recent efforts towards the identification and pharmacological characterization of novel histamine H3 antagonists will be discussed.

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