Melatonin receptor agonist

Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The discovery and development of melatonin receptor agonists was motivated by the need for more potent analogues than melatonin, with better pharmacokinetics and longer half-life. Melatonin receptor agonists were developed with the melatonin structure as a model. Melatonin receptor agonists are analogues of melatonin that bind to and activate the melatonin receptor. Agonists of the melatonin receptor have a number of therapeutic applications including treatment of sleep disorders and depression. The discovery and development of melatonin receptor agonists was motivated by the need for more potent analogues than melatonin, with better pharmacokinetics and longer half-life. Melatonin receptor agonists were developed with the melatonin structure as a model. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types. The binding of the agonists to the receptors has been investigated since 1986, yet is still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. 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. High-affinity melatonin binding sites were pharmacologically characterized in the bovine brain in 1979. The first melatonergic receptor was cloned from melanophores of Xenopus laevis in 1994. In 1994-1995 the melatonin receptors were characterized and cloned in the human being by Reppert and colleagues. TIK-301 (PD-6735, LY-156,735) has been in phase II clinical trial in the United States (US) since 2002. The FDA granted TIK-301 orphan drug designation in May 2004, to use as a treatment for circadian rhythm sleep disorder in blind individuals without light perception and individuals with tardive dyskinesia. In 2005 ramelteon (Rozerem®) was approved in the US indicated for treatment of insomnia, characterized as difficulty with falling asleep, in adults. 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). Products containing melatonin are available as a dietary supplement in the United States and Canada. In 2009 agomelatine (Valdoxan®, Melitor®, Thymanax®) was also approved in Europe and is indicated for the treatment of major depressive disorder in adults. Tasimelteon completed the phase III clinical trial in the United States for primary insomnia in 2010. 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®. 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. 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. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorylation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP. As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell. When melatonin receptor agonists activate their receptors it causes numerous physiological processes. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. The SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions. 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. 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. This led to further research on the molecule, mainly substitution of the aromatic ring. Various modulations showed promising activity, especially the naphthalene ring which is present in agomelatine (figure 1). Other ring systems have also showed melatonin agonist activity. Amongst them are indane which is present in ramelteon (figure 1) and the ring system of tasimelteon (figure 1). The general structure of melatonin is the indole ring with methoxy group in position 5 (5-methoxy group) and acylaminoethyl side-chain in position 3. The two side-chains are important for binding to and activating the receptors. The indole ring has been evaluated at all positions by the effect of substitutions as seen in figure 1. Each position is further explained below: