Sleep disorders melatonin agonist

Melatonin receptor agonists in the treatment of sleep disorders... 

Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed in Ann. Rep. Med. Chem., volume 39 [29]. Since then, ramelteon has been approved, representing an important milestone for the proof of concept of this target, and has opened new possibilities for research. 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observations have been applied to the development of ramel-teon, a prescription hypnotic, which is an agonist at melatonin receptors (see Chapter 22). 

In the course of developing the melatonin agonist 1 (Fig. 1), potentially indicated for the treatment of sleep disorders, we evaluated approaches to the chiral cyclopropane intermediates 2 a and 2 b based on both classical resolution and asymmetric induction. Conceptually, these intermediates could be derived from di-hydrobenzofurans 3, 4 and 5 each of these was used at one stage or another during our research and development work. 

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