Pineal hormone melatonin is widely used in the treatment of disorders of circadian rhythms. The presence of melatonin receptors in various animal tissues motivates the use of this hormone in some other diseases. For this reason, in recent years investigators continued the search for synthetic analogues of melatonin which are metabolically stable and selective to receptors. This review includes recent information about the most famous melatonin analogues, their structure, properties, and physiological features of the interaction with melatonin receptors.
Almost since its opening in the mid-20th century epiphyseal hormone melatonin is seen as a valuable pharmacological agent. The results of the subsequent thorough and comprehensive study of the biochemical and physiological effects of melatonin have only confirmed this view. The positive results of the use of melatonin were obtained for the treatment of insomnia, circadian rhythm disorders associated with shift work, the change of time zones, and seasonal disorders [
Experts believe that one of the limiting factors is the short half-life of melatonin. In recent years, two approaches to this problem are emerged. The first way is connected with the improvement of the pharmacokinetics due to the creation of medicinal forms of prolonged action. For example, the company Neurim Pharmaceuticals has produced drug called Circadin, mimicking physiological profile of epiphyseal hormone secretion. The second path involves the creation of more stable agonists, which also could selectively bind with a specific type of melatonin receptor. At present, this area is considered to be more promising. This topic is the focus of this review.
Melatonin (N-acetyl-5-methoxytryptamine) is a heterocyclic compound, derivative of indole (Figure
Structure of melatonin.
In mammals, melatonin controls the set of physiological functions. It participates in the formation of circadian and seasonal rhythms [
Melatonin is synthesized in the epiphysis from the essential amino acid tryptophan. First, by hydroxylation and decarboxylation serotonin is formed, which is then N-acetylated and O-methylated. The rate of melatonin synthesis is limited by the enzyme serotonin-N-acetyltransferase [
Epiphysis is not the only organ secreting melatonin. Cells producing this indole are found in the retina, Harderian gland, gastrointestinal tract, pancreas, respiratory tract, and thyroid and adrenal glands [
Newly synthesized melatonin is not accumulated in endocrine cells. It leaves the place of synthesis easily because of its ability to passively diffuse through the cell membrane. In blood, melatonin binds to proteins, preferably with a serum albumin and acidic glycoprotein
As some compounds of indole nature, melatonin has a short half-life (30–50 minutes, depending on the species). In the liver, biotransformation is carried out by hydroxylation and subsequent formation of conjugates with sulfuric and glucuronic acids. In the other organs the hormone metabolism proceeds otherwise. The most common is deacetylation to form a 5-methoxytryptamine. In the retina, this compound is converted into 5-methoxyindoleacetic acid and 5-methoxytryptophol [
In recent times a number of melatonin receptors have been identified. The greatest certainty is achieved for membrane (MT1 and MT2) and nuclear (RZR/ROR
Receptors and binding sites of melatonin are distributed throughout the body. Their greatest number is noted in various brain structures, endocrine glands, and some peripheral organs [
In the cells of various mammalian species the two types of membrane receptors are revealed, MT1 and MT2, formerly known as
In humans, the length of polypeptide chains is 350 and 362 amino acids, respectively. MT1 and MT2 molecules have high amino acid sequence homology (approximately 60%) [
MT1 and MT2 receptors have high affinity to melatonin. For molecules isolated from human cells,
Recent works demonstrated polymorphisms of the MT1/MT2 receptors and related genes in human and animals. However, these mutations did not have clear phenotypic expression [
Membrane receptors are associated with G-protein; however, depending on the tissue type intracellular signaling mechanisms may differ considerably. The most common is the suppression of cAMP synthesis by Gi-proteins both sensitive and insensitive to pertussis toxin [
The MT1 and MT2 receptors may be coupled with
Another potentially important mechanism of melatonin signal transduction via the MT2 is the influence on the level of cGMP. While some researchers have observed an increase in the number of cGMP, probably due to inhibition of phosphodiesterase [
Through the MT1 and MT2 melatonin activates potassium channels GIRK (G protein-coupled inwardly rectifying potassium channels) [
Molecules of MT1 and MT2 as many receptors coupled to G-proteins are capable of dimerization. MT1 homodimers and MT1/MT2 heterodimers are formed in several times lighter than homodimers MT2 [
Recent studies have shown that MT1 and MT2 form complexes with certain intracellular proteins. Some of them are associated with both receptors (filamin and IRS4, insulin receptor substrate 4), while others show greater selectivity. MT1 receptor specifically interacts with phosphodiesterase, protein elongation factor EEF-1B
It is believed that modification of the affinity and number of melatonin receptors is an important component of the mechanism which regulates the circadian rhythm. Prolonged exposure to hormone leads to desensitization of membrane receptors [
Nuclear receptors for melatonin RZR/ROR
The nuclear receptors have a typical domain organization. C-terminal domain provides the ligand attaching. It is also responsible for receptor dimerization. However, unlike other members of the family of nuclear receptors, RZR/ROR
It is assumed that the nuclear melatonin receptors are responsible for the manifestation of the hormone immunomodulatory action as it enhances the syntheses of interleukins and
The polypeptide chain of this protein is 618 amino acid residues in length. Binding site GPR50 has a high (about 45%) amino acid sequence homology with MT1 and MT2 and structural features specific for the melatonin receptors [
Discovery of this binding site, found in the liver, kidney, and brain [
As a result of numerous studies MT3 was identified as quinone reductase QR2 (EC 1.10.99.2). The biological role of the enzyme is unknown but it is assumed that it is involved in neutralization of toxic quinones. On this basis it has been hypothesized that antioxidant properties of melatonin are related with the activity of QR2 [
In the past two decades, a large number of ligands for melatonin receptors have been synthesized. Structure-activity relationships (SARs) of melatonin derivatives have been comprehensively analyzed [
Large-scale search for effective melatonin receptor agonists was started in the late 80s. The work was done on tissue samples, which contain, as it turned out later, a heterogeneous set of melatonin binding sites, so the dependence of the “structure-activity” was considered without taking into account the differences in the structure of the receptor [
Synthetic ligands at melatonin receptors.
Number | Compound* | Type of ligand | Reference |
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Melatonin derivatives | |||
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Agonist |
[ |
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Agonist MT1, |
[ |
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Agonist MT3 | [ |
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Tri- and tetracyclic compounds | |||
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Antagonist MT2 | [ |
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Agonist MT2 | [ |
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Agonist |
[ |
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Agonist |
[ |
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Naphthalene and tetralin analogues | |||
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Agonist |
[ |
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Antagonist MT2 | [ |
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“Dimeric ligands” | |||
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Agonist MT1 | [ |
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Antagonist MT1 | [ |
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Thiazolidine analogues | |||
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Agonist RZR/ROR | [ |
First agonists were obtained by modification of melatonin structure. These agonists were used to specify positions important for interaction with the receptor. Position 6 is determinative for binding as well as methoxy group (position 5), and amide group of side chain. Introduction into the molecule of large substituents in the positions 1 and
Positive results are shown for molecules with partial restriction of conformational mobility [
Search of selective agonists is essential for determination of the role of each receptor type in the implementation of the biological effects of melatonin. Although significant structural similarity in MT1 and MT2, in recent years ligands were collected which specifically bind to one of these receptors. For such a highly selective ligands, the
Currently, only membrane melatonin receptor agonists have clinical interest. Although the number of synthesized and tested ligands of MT1/MT2 amounts to hundreds, only a few compounds have reached the stage of clinical trials. Ramelteon (Rozerem) was developed by the pharmaceutical company Takeda and approved in the US in 2005. Agomelatine (Valdoxan, Melitor, Thymanax) was developed by the pharmaceutical company Servier and approved in Europe in 2009. Two melatonin agonists, Tasimelteon and TIK-301, have received orphan drug designation and are in clinical trials in the United States. Tasimelteon was developed by Vanda Pharmaceuticals, and phase III of its clinical trial was completed in 2010. TIK-301 was designed originally by Eli Lilly and Company, and since 2007 the trials have been undergone in Tikvah Pharmaceuticals. In February 2013, Neurim Pharmaceuticals reported positive results of phase II of trials for piromelatine (Neu-P11).
Ramelteon, N-
When orally administered, ramelteon is rapidly absorbed. Peak of drug concentration in plasma is achieved in approximately 1 h after administration [
During the preclinical and clinical trials it was shown that ramelteon promotes sleep without causing any significant side effects. The drug does not affect the coordination of movements, memory, and learning ability. It has no sedative effect, so sleep induced by the drug is indistinguishable from natural sleep [
Due to proven clinical effectiveness and safety, ramelteon is considered as the fourth-generation drug for the treatment of primary insomnia and insomnia associated with circadian rhythms [
Agomelatine, N-[2-(7-Methoxy-1-naphthyl)ethyl], is a derivative of naphthalene. The drug has a high affinity to MT1/MT2 receptors comparable with melatonin (Table
When administered per os, agomelatine, as well as ramelteon, has low bioavailability. Peak of drug concentration in blood plasma is observed within 1-2 hours. Almost all of the molecules of agomelatine are associated with blood proteins. Biotransformation of agomelatine occurs mainly in the liver to form hydroxylated and demethylated derivatives. Four metabolites of agomelatine are identified: 3-hydroxy-, 7-methoxy-, 7-desmethyl-, and dihydrodiol-agomelatine [
Binding to MT1/MT2 receptors, agomelatine synchronizes circadian rhythms in animals with delayed sleep phase syndrome [
Tasimelteon (VEC-162, BMS-214778) is a derivative of propanamide, N-[[(1R, 2R)-2-(2,3-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl] propanamide. The drug demonstrates a higher affinity for melatonin receptors than natural ligand (Table
In plasma, tasimelteon circulates predominantly in protein-bound form (<91%). The drug is distributed throughout the body. Its metabolism occurs in the liver by hydroxylation and dehydrogenation [
In clinical trials, tasimelteon improved sleep latency, sleep efficiency, and wake after sleep onset (i.e., sleep maintenance). The drug exhibits a good safety profile with no significant side effects in comparison with placebo [
Neu-P11 (piromelatine, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2-carboxamide) is a new potential drug for the treatment of insomnia [
After half a century of studying melatonin, it is considered as an integral part of the homeostatic mechanisms of the organism and a hormone involved in regulating a large number of various physiological processes. Definition of the melatonin receptors structure, the discovery of signaling mechanisms, the establishment of cell lines and animal models, and synthesizing only MT1 or MT2, all this contributed to the understanding of the role of melatonin and its receptors in the modulation of visual, circadian, endocrine, and immune functions.
The accumulated information served as a catalyst for the creation of synthetic melatonergic ligands. Over the past three decades there were synthesized and tested hundreds of molecules, which specifically bind to melatonin receptors. Functional groups of melatonin, which are critical for binding to the receptors, have been clarified that allowed a realization of the systematic approach to the synthesis of new ligands. Radiolabeled ligands, selective agonists and antagonists to MT1 and MT2 receptors, were already used as a tool for studying of melatonin functioning. Some melatonin agonists have obvious pharmacological value. Currently five compounds (ramelteon, agomelatine, tasimelteon, Neu-P11, and TIK-301) have reached a stage of clinical trials, two of them (ramelteon and agomelatine) gained approval for clinical use as drugs for the treatment of insomnia and violations of circadian rhythms.
However, the development of the new melatoninergic ligands is far from complete. It is necessary to expand the spectrum of high-selective agonists and antagonists, which could be used both for scientific research and in medical practice. It seems to be promising a study of synergistic relationships between melatonin receptors and receptor of neurotransmitters, such as serotonin. This dual activity detected in agomelatine made it effective in treatment of insomnia caused by depression. Another important direction is the search of melatonergic ligands with other pharmacological activities. Based on the biological role of melatonin, among its ligands we can expect the existence of potential drugs for treatment of oncological diseases and metabolic and endocrine disorders.
The authors declare that there is no conflict of interests regarding the publication of this paper.