Agomaletina

Melatonin and Melatonin Analogues
Shantha M.W. Rajaratnam, PhDa,b,c,*, Daniel A. Cohen, MDb,d,e, Naomi L. Rogers, PhDf
KEYWORDS
 Melatonin  Melatonin agonist  Circadian rhythm  Sleep  Ramelteon  Tasimelteon  Agomelatine  PD-6735

Over the past 25 years, there has been substantial growth in the field of melatonin and melatonin analogues.1 Following the first demonstration thatexogenous melatonin can entrain the mammalian circadian system2 and the discovery of the phase-shifting and sleep-promoting properties of the hormone in humans,3 several groups have demonstrated the potential for melatonin to be used as a treatment for circadian rhythm sleep disorders (CRSDs). Clinical development of melatonin agonists for sleep and psychiatric disorders has also provided significantmomentum to this field. There is increasing interest in the use of melatonin-like compounds in the treatment of primary insomnia; however, the mechanisms underlying these effects remain unclear. Herein we review the role of melatonin and melatonin receptors in the circadian regulation of sleep, the phase-shifting and sleep-promoting properties of exogenous melatonin, and some of the melatoninagonists that have been developed or are under development for the treatment of primary insomnia, CRSDs, and major depression.

ENDOGENOUS MELATONIN
The hormone melatonin (5-methoxy-N-acetyltryptamine) is synthesized and secreted by the pineal

gland under the control of the circadian timing system. In normally entrained individuals, melatonin secretion into the bloodstream occurs primarily atnight, with negligible levels secreted during the day. The circadian pacemaker, located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus, mediates melatonin secretion via GABAergic inhibition and glutamatergic stimulation of the paraventricular nucleus and sympathetic noradrenergic stimulation of the pineal gland.4–7 The physiologic roles of melatonin are not fully understood; however,it is widely recognized that melatonin modulates the circadian system, and it has been implicated in the control of the sleepwake system as well as a range of other processes.8 The role of melatonin in mediating photoperiodic responses is well characterized but is not discussed herein. Melatonin administration is associated with changes in SCN neural activity, energy metabolism, and intrinsiccellular processes. Several years ago it was demonstrated that SCN-lesioned animals do not entrain to daily injections of melatonin,9 indicating that the SCN is necessary for entrainment. A single in vivo administration of melatonin to rats phase shifted the rhythm of light-induced c-fos expression in the SCN,10

Sleep Med Clin 4 (2009) 179–193 doi:10.1016/j.jsmc.2009.02.007 1556-407X/09/$ – seefront matter ª 2009 Elsevier Inc. All rights reserved.

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a School of Psychology, Psychiatry and Psychological Medicine, Monash University, Building 17, Clayton, Victoria 3800, Australia b Division of Sleep Medicine, Department of Medicine, Brigham and Women’s Hospital, 221 Longwood Avenue, Boston, MA 02115, USA c Division of Sleep Medicine, Harvard Medical School, 221Longwood Avenue, Boston, MA 02115, USA d Harvard Medical School, 25 Shattuck Street, Boston, MA 02215, USA e Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, KS 450, Boston, MA 02215, USA f Brain and Mind Research Institute, University of Sydney, 94 Mallett Street, Building F, Level 5, Camperdown NSW 2050, Australia * Corresponding author. School of Psychology,Psychiatry and Psychological Medicine, Monash University, Building 17, Clayton, Victoria 3800, Australia. E-mail address: shantha.rajaratnam@med.monash.edu.au (S.M.W. Rajaratnam).

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indicating that melatonin administration immediately resets SCN rhythmicity. Melatonin injections also affect levels of 2-deoxyglucose uptake in the SCN, with the direction of the response...