Chapter 5 Recent Advances in the Treatment of Insomnia

Publisher Summary This chapter discusses current drug therapy for insomnia, which includes γ-aminobutyric acid A (GABA A ) receptor agonists, melatonin receptor agonists, over-the-counter (OTC) products, antidepressants and antihistamines. GABA A receptor agonists used for insomnia fall into two classes: ‘Z-drugs' and benzodiazepines. Zolpidem, a ‘Z-drug’, is the market leading compound in this therapeutic group. ‘Z-drugs' are the most frequent treatment for insomnia with the compounds zolpidem, zaleplon and zopiclone marketed for transient insomnia and eszopiclone (S-isomer of zopiclone) for both transient and chronic insomnia. Imidazo[1,2-a]pyridine, the central scaffold in Zolpidem, has been extensively explored in the search for insomnia drugs. Melatonin receptor agonists and their relevance for the treatment of sleep disorders and major depression have been previously reviewed. 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. Compound LY-156735/PD-6735 is a melatonin MT1 and MT2 agonist currently undergoing phase II trials for the improvement of sleep onset latency in patients with primary insomnia. The chapter also discusses orexin receptor antagonists such as N-quinolinyl-N0-phenyl ureas and N-quinolinyl cynamamides; 1,2,3,4-tetrahydroisoquinolines, piperazines and morpholines; and pyrrolo- and pyrido[2,1-b]quinazolinones and 3,4-dihydroquinoxalin-3-ones followed by histaminergic and serotoninergic modulators.