Hindawi Publishing Corporation ISRN Biochemistry Volume 2014, Article ID 843478, 11 pages http://dx.doi.org/10.1155/2014/843478 Review Article Synthetic Melatoninergic Ligands: Achievements and Prospects N. V. Kostiuk,1 M. B. Belyakova,2 D. V. Leshchenko,2 V. V. Zhigulina,2 and M. V. Miniaev3 1 Department of Biology, Tver State Medical Academy, 4 Sovetskaya Street, Tver 170100, Russia 2 DepartmentofBiochemistry,TverStateMedicalAcademy,4SovetskayaStreet,Tver170100,Russia 3 Research Center, Tver State Medical Academy, 4 Sovetskaya Street, Tver 170100, Russia Correspondence should be addressed to M. B. Belyakova; [email protected] Received 5 November 2013; Accepted 16 January 2014; Published 23 February 2014 Academic Editors: A. Azem and Z. Debyser Copyright © 2014 N. V. Kostiuk et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction 2. Melatonin Almost since its opening in the mid-20th century epiphyseal 2.1. Structure and Biological Function of Melatonin. Mela- hormone melatonin is seen as a valuable pharmacological tonin (N-acetyl-5-methoxytryptamine) is a heterocyclic agent. The results of the subsequent thorough and compre- compound, derivative of indole (Figure 1). hensive study of the biochemical and physiological effects of In mammals, melatonin controls the set of physiological melatonin have only confirmed this view. The positive results functions. It participates in the formation of circadian and of the use of melatonin were obtained for the treatment of seasonal rhythms [6–8], behavioral reactions [9, 10], and insomnia, circadian rhythm disorders associated with shift adaptation [11, 12]. It plays an important role in the regulation work, the change of time zones, and seasonal disorders [1– of reproductive function [13], the cardiovascular system [14, 3]. The expediency of the use of melatonin is shown in 15], immune reactions [16, 17], the restriction of the processes the treatment of cardiovascular diseases, cancer, and other of cell proliferation, and tumor growth [18, 19]. Accumulated diseases [4, 5]. However, the widespread introduction of the experimental data evidently demonstrate the influence of the drug in clinical practice has not been observed. pineal hormone on the state of protein, lipid, carbohydrate, Experts believe that one of the limiting factors is the short and pigment metabolism [20–23]. The implementation of half-life of melatonin. In recent years, two approaches to this such diverse effects of melatonin is provided by the existence problem are emerged. The first way is connected with the of numerous receptors and binding sites for the hormone. improvement of the pharmacokinetics due to the creation of medicinal forms of prolonged action. For example, the 2.2. Melatonin Biosynthesis. Melatonin is synthesized in the company Neurim Pharmaceuticals has produced drug called epiphysis from the essential amino acid tryptophan. First, Circadin, mimicking physiological profile of epiphyseal hor- by hydroxylation and decarboxylation serotonin is formed, mone secretion. The second path involves the creation of whichisthenN-acetylatedandO-methylated.Therateof more stable agonists, which also could selectively bind with melatonin synthesis is limited by the enzyme serotonin-N- a specific type of melatonin receptor. At present, this area is acetyltransferase [1, 24]. The cascade of reactions is trig- considered to be more promising. This topic is the focus of geredinthedarknessasaresultofactivationof1-and this review. 1-adrenoreceptors of pinealocytes by noradrenaline. This 2 ISRN Biochemistry O (MT1 and MT2) and nuclear (RZR/ROR and RZR/ROR) receptors. Discussion regarding other melatonin binding sites NH CH3 is still far from complete. Binding sites were found in different 4 parts of the cell: in the membranes (GPR50), in the cytosol H CO 3 3 (MT3),andinthemitochondria[31]. 5 Receptors and binding sites of melatonin are distributed 2 throughout the body. Their greatest number is noted in vari- 6 ous brain structures, endocrine glands, and some peripheral N 1 H organs [32, 33]. The distribution of receptors is organospe- 7 cific. Several types of binding sites may occur in the cells of Figure 1: Structure of melatonin. one organ. MT1 receptors are predominant [1]. Density and affinity of receptors undergo significant changes during the day. In the daytime, when the concentration of melatonin mechanismofregulationoftheglandsyntheticactivity decreases, the number of its receptors is increasing [32, 33]. provides a circadian rhythm of melatonin secretion with a peak at night period [1, 25]. It was found that the effect of neurotransmitter is associated with increased transport of 3.1. Membrane Receptors MT1 and MT2. In the cells of vari- tryptophan in pinealocytes, formation of the terminal synthe- ous mammalian species the two types of membrane receptors sizing enzyme hydroxy-O-methyltransferase, and activation are revealed, MT1 and MT2, formerly known as Mel1 and of serotonin acetylation with simultaneous suppression of its a Mel1b.MT1 is found in the hypothalamus, the pituitary gland, oxidative deamination [26]. Synthesis of melatonin is affected cerebral cortex, thalamus, hippocampus, cerebellum, cornea by dopamine, glutamate, GABA, and serotonin. These com- and retina, arteries, heart, lungs, liver, kidney, adrenal gland, pounds alter the activity of serotonin-N-acetyltransferase. skin, and B and T lymphocytes [1, 33, 34]. MT2 receptors are Exogenous melatonin can also modulate the synthesis by localized in the hippocampus, the cerebellum, retina, arteries, both inhibiting and stimulating it [26, 27]. heart, lungs, liver, small intestine, and skin [1, 32, 35]. Epiphysis is not the only organ secreting melatonin. Cells In humans, the length of polypeptide chains is 350 and producing this indole are found in the retina, Harderian 362 amino acids, respectively. MT1 and MT2 molecules gland, gastrointestinal tract, pancreas, respiratory tract, and havehighaminoacidsequencehomology(approximately thyroid and adrenal glands [26, 27]. Some scientists believe 60%) [28]. In accordance with the characteristics of their that extrapineal sources account for less than 20% of the spatial structure, the MT1/MT2 receptors belong to the body’s melatonin, and others consider enterochromaffin cells family of rhodopsin/2-adrenergic receptors [36]. They are asthemainsourceofthehormone[26]. basedonseventransmembrane-helices connected by a Newly synthesized melatonin is not accumulated in series of intra- and extracellular loops [34]. The extracellular endocrine cells. It leaves the place of synthesis easily because N-terminal fragment has the glycosylation sites, and an of its ability to passively diffuse through the cell membrane. In intracellular C-terminal fragment includes phosphorylation blood, melatonin binds to proteins, preferably with a serum sites [31, 37]. The palmitic acid residue can be attached to the albumin and acidic glycoprotein 1[28]. cysteine residue of the fourth (intracellular) loop [38]. MT1 and MT2 receptors have high affinity to melatonin. 2.3. Degradation of Melatonin. As some compounds of For molecules isolated from human cells, values are 80.7 indole nature, melatonin has a short half-life (30–50 min- and 383 pM, respectively [39]. Molecular mechanisms of utes, depending on the species). In the liver, biotransfor- melatonin binding to its receptors are far from sufficiently mation is carried out by hydroxylation and subsequent studied. It is assumed that the binding of 5-methoxyl group formation of conjugates with sulfuric and glucuronic acids. of melatonin may involve residues of histidine (His195 in the In the other organs the hormone metabolism proceeds MT1 and His208 in the MT2) and valine (Val-192) of the fifth otherwise. The most common is deacetylation to form transmembrane helix. The structure of pocket for binding a 5-methoxytryptamine. In the retina, this compound is of melatonin’s N-acetyl group appears to differ for two converted into 5-methoxyindoleacetic acid and 5-methox- receptors. In the MT1 an important role belongs to the serine ytryptophol [29]. Mononuclear leukocytes are capable of residues (Ser110 and Ser114) in the third transmembrane regenerating N-acetyl serotonin and serotonin from mela- helix, whereas asparagine (Asn175) of the fourth helix has tonin [29]. While in brain cells the opening of melatonin greater importance in the MT2 [28]. pyrrole ring leads to formation of kynuramines [26]. Products Recent works demonstrated polymorphisms of the of degradation are mostly excreted with the urine. Studies MT1/MT2 receptors and related genes in human and animals. concerning the exchange of melatonin are reviewed fully However, these mutations did not have clear phenotypic [25, 28, 30]. expression [28, 40]. Membrane receptors are associated with