Melatonin receptor agonist

In 1917 McCord and Allen discovered melatonin itself. In 1958, Aaron B. Lerner and his colleagues isolated the substance N-acetyl-5-methoxytryptamine and named it melatonin. TIK-301 (PD-6735, LY-156735) has been in phase II clinical trial in the United States (US) since 2002. 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, and final FDA approval for the same purpose was achieved in January 2014 under the trade name Hetlioz. ==Melatonin receptors==

In humans there are two subtypes of melatonin receptors targeted by melatonin agonists, MT1 and MT2. They are G protein-coupled receptors and are expressed in various tissues of the body, together or singly. Melatonin receptors have been identified in the cardiovascular system. Evidence from animal studies points to a dual role of melatonin in the vasculature. Activation of MT1 receptors mediates vasoconstriction and the activation of MT2 receptors mediates vasodilation. Melatonin is involved in regulating immune responses in both human and animals through activation of both MT1 and MT2 receptors. 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. This is not a complete list since many of the possible processes need further confirmation. ==Drug design and development==

Receptors and the structure of melatonin are known. 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. TIK-301 (Figure 1) is an agonist of the early classes. It is very similar to melatonin and has made it to clinical trials. An example of approved drug with naphthalene ring is agomelatine. The aromatic ring and the ethyl side-chain hold the correct distance between those two groups, as the correct distance is the key to good binding and more important than what type of aromatic ring system the analogue contains. Therefore, it is possible to use different ring systems in melatonin receptor analogues, if the distance is right. Substituents in positions 1 or 2 of the indole scaffold projecting outside of the aromatic cycle plane increase selectivity toward the MT2 receptor, resulting in the most selective melatonin receptor ligands and simultaneously reducing receptor activation. The melatonin receptors consist of proteins around 40 kDa each. The MT1 receptor encodes 350 amino acids and the MT2 encodes 362 amino acids. The binding of melatonin and its analogues is now understood through X-ray crystal structures published in 2019. The binding space for melatonin and analogues on the MT1 receptor is smaller than on the MT2. Despite its structural similarities with melatonin, serotonin is not able to bind melatonin receptor due to the polar first amine group and the lack of an aspartate in position 3.32 within melatonin receptor orthosteric site. ==Current status==

There are three melatonin agonists on the market today (February 2014); ramelteon (Rozerem), agomelatine (Valdoxan, Melitor, Thymanax) and tasimelteon (Hetlioz). Ramelteon was developed by Takeda Pharmaceutical Company and approved in the United States in 2005. Agomelatine was developed by the pharmaceutical company Servier and approved in Europe 2009. Tasimelteon was developed by Vanda Pharmaceuticals and completed the phase III trial in 2010. It was approved by the FDA on January 31, 2014, for the treatment of non-24-hour sleep–wake disorder in totally blind individuals. 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. Additionally, Neurim Pharmaceuticals reported the results of a positive phase II trial of its investigational compound piromelatine (Neu-P11) in February 2013. No antagonists or selective ligands are currently reported in clinical studies. == References ==