[1] Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression.

[1] In 2005 ramelteon (Rozerem) was approved in the US indicated for treatment of insomnia, characterized as difficulty with falling asleep, in adults.

[citation needed] Melatonin in the form of prolonged release (trade name Circadin) was approved in 2007 in Europe (EU) for use as a short-term treatment, in patients 55 years or older, for primary insomnia (poor quality of sleep).

In 2009 agomelatine (Valdoxan, Melitor, Thymanax) was also[clarification needed] approved in Europe and is indicated for the treatment of major depressive disorder in adults.

[citation needed] Tasimelteon completed the phase III clinical trial in the United States for primary insomnia in 2010.

[9] The Food and Drug Administration (FDA) granted tasimelteon orphan drug designation status for blind individuals without light perception with non-24-hour sleep–wake disorder in January the same year,[citation needed] and final FDA approval for the same purpose was achieved in January 2014 under the trade name Hetlioz.

[2] MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus (SCN) of the hypothalamus, hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens.

[2][5] MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system.

[1][2][4] The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.

[2][4] MT1 and MT2 receptors are widespread in the eye and are involved in regulating aqueous humor secretion, which is important for glaucoma, and in phototransduction.

Therefore, researchers started to investigate modulations of the core structure to develop better agonists than melatonin; more potent, with better pharmacokinetics and longer half-life.

Though the melatonin receptor was not characterized and cloned in the human being until 1994 it was possible to start carrying out binding studies in various tissues before that time.

In fact, it is possible to replace the indole with other aromatic ring systems (naphthalene, benzofuran, benzothiazole, indane, tetraline, tetrahydroquinolines).

[4][5] Researchers agree that the oxygen in the group binds to histidine (His) residues in transmembrane 5 (TM5) domain of the receptor with a hydrogen bond; His1955.46 in MT1 and His2085.46 in MT2.

[1][3][4] In past years, mutagenesis of residues involved in the binding site was not fully successful in the determination of the polar key contacts [13] established by the methoxy group and the ethyl-amide side chain.

There are three melatonin agonists on the market today (February 2014); ramelteon (Rozerem), agomelatine (Valdoxan, Melitor, Thymanax) and tasimelteon (Hetlioz).

[10] One melatonin agonist has received orphan drug designation and is going through clinical trials in the United States: TIK-301.

In July 2010 in Europe, prolonged-release melatonin (Circadin, Neurim Pharmaceuticals) was approved for use for 13 weeks for insomnia patients over 55 years old.

[20] Additionally, Neurim Pharmaceuticals reported the results of a positive phase II trial of its investigational compound piromelatine (Neu-P11) in February 2013.