reviewarticle synthetic melatoninergic ligands: achievements...

Review ArticleSynthetic Melatoninergic Ligands Achievements and Prospects

N V Kostiuk1 M B Belyakova2 D V Leshchenko2 V V Zhigulina2 and M V Miniaev3

1 Department of Biology Tver State Medical Academy 4 Sovetskaya Street Tver 170100 Russia2 Department of Biochemistry Tver State Medical Academy 4 Sovetskaya Street Tver 170100 Russia3 Research Center Tver State Medical Academy 4 Sovetskaya Street Tver 170100 Russia

Correspondence should be addressed to M B Belyakova mayabeyandexru

Received 5 November 2013 Accepted 16 January 2014 Published 23 February 2014

Academic Editors A Azem and Z Debyser

Copyright copy 2014 N V Kostiuk et al This is an open access article distributed under the Creative Commons Attribution Licensewhich 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 receptorsin various animal tissues motivates the use of this hormone in some other diseases For this reason in recent years investigatorscontinued the search for synthetic analogues of melatonin which are metabolically stable and selective to receptors This reviewincludes recent information about the most famous melatonin analogues their structure properties and physiological features ofthe interaction with melatonin receptors

1 Introduction

Almost since its opening in the mid-20th century epiphysealhormone melatonin is seen as a valuable pharmacologicalagent The results of the subsequent thorough and compre-hensive study of the biochemical and physiological effects ofmelatonin have only confirmed this viewThe positive resultsof the use of melatonin were obtained for the treatment ofinsomnia circadian rhythm disorders associated with shiftwork the change of time zones and seasonal disorders [1ndash3] The expediency of the use of melatonin is shown inthe treatment of cardiovascular diseases cancer and otherdiseases [4 5] However the widespread introduction of thedrug in clinical practice has not been observed

Experts believe that one of the limiting factors is the shorthalf-life of melatonin In recent years two approaches to thisproblem are emerged The first way is connected with theimprovement of the pharmacokinetics due to the creationof medicinal forms of prolonged action For example thecompany Neurim Pharmaceuticals has produced drug calledCircadin mimicking physiological profile of epiphyseal hor-mone secretion The second path involves the creation ofmore stable agonists which also could selectively bind witha specific type of melatonin receptor At present this area isconsidered to be more promising This topic is the focus ofthis review

2 Melatonin

21 Structure and Biological Function of Melatonin Mela-tonin (N-acetyl-5-methoxytryptamine) is a heterocycliccompound derivative of indole (Figure 1)

In mammals melatonin controls the set of physiologicalfunctions It participates in the formation of circadian andseasonal rhythms [6ndash8] behavioral reactions [9 10] andadaptation [11 12] It plays an important role in the regulationof reproductive function [13] the cardiovascular system [1415] immune reactions [16 17] the restriction of the processesof cell proliferation and tumor growth [18 19] Accumulatedexperimental data evidently demonstrate the influence of thepineal hormone on the state of protein lipid carbohydrateand pigment metabolism [20ndash23] The implementation ofsuch diverse effects of melatonin is provided by the existenceof numerous receptors and binding sites for the hormone

22 Melatonin Biosynthesis Melatonin is synthesized in theepiphysis from the essential amino acid tryptophan Firstby hydroxylation and decarboxylation serotonin is formedwhich is then N-acetylated and O-methylated The rate ofmelatonin synthesis is limited by the enzyme serotonin-N-acetyltransferase [1 24] The cascade of reactions is trig-gered in the darkness as a result of activation of 120572

1- and

1205731-adrenoreceptors of pinealocytes by noradrenaline This

Hindawi Publishing CorporationISRN BiochemistryVolume 2014 Article ID 843478 11 pageshttpdxdoiorg1011552014843478

2 ISRN Biochemistry

1

2

34

5

6

7

NH

NH

O

120573 CH3

H3CO

Figure 1 Structure of melatonin

mechanism of regulation of the gland synthetic activityprovides a circadian rhythm of melatonin secretion with apeak at night period [1 25] It was found that the effect ofneurotransmitter is associated with increased transport oftryptophan in pinealocytes formation of the terminal synthe-sizing enzyme hydroxy-O-methyltransferase and activationof serotonin acetylation with simultaneous suppression of itsoxidative deamination [26] Synthesis ofmelatonin is affectedby dopamine glutamate GABA and serotonin These com-pounds alter the activity of serotonin-N-acetyltransferaseExogenous melatonin can also modulate the synthesis byboth inhibiting and stimulating it [26 27]

Epiphysis is not the only organ secreting melatonin Cellsproducing this indole are found in the retina Harderiangland gastrointestinal tract pancreas respiratory tract andthyroid and adrenal glands [26 27] Some scientists believethat extrapineal sources account for less than 20 of thebodyrsquos melatonin and others consider enterochromaffin cellsas the main source of the hormone [26]

Newly synthesized melatonin is not accumulated inendocrine cells It leaves the place of synthesis easily becauseof its ability to passively diffuse through the cellmembrane Inblood melatonin binds to proteins preferably with a serumalbumin and acidic glycoprotein 1205721 [28]

23 Degradation of Melatonin As some compounds ofindole nature melatonin has a short half-life (30ndash50 min-utes depending on the species) In the liver biotransfor-mation is carried out by hydroxylation and subsequentformation of conjugates with sulfuric and glucuronic acidsIn the other organs the hormone metabolism proceedsotherwise The most common is deacetylation to forma 5-methoxytryptamine In the retina this compound isconverted into 5-methoxyindoleacetic acid and 5-methox-ytryptophol [29] Mononuclear leukocytes are capable ofregenerating N-acetyl serotonin and serotonin from mela-tonin [29] While in brain cells the opening of melatoninpyrrole ring leads to formation of kynuramines [26] Productsof degradation are mostly excreted with the urine Studiesconcerning the exchange of melatonin are reviewed fully[25 28 30]

3 Melatonin Receptors

In recent times a number of melatonin receptors have beenidentified The greatest certainty is achieved for membrane

(MT1and MT

2) and nuclear (RZRROR120572 and RZRROR120573)

receptors Discussion regarding othermelatonin binding sitesis still far from complete Binding sites were found in differentparts of the cell in the membranes (GPR50) in the cytosol(MT3) and in the mitochondria [31]

Receptors and binding sites of melatonin are distributedthroughout the body Their greatest number is noted in vari-ous brain structures endocrine glands and some peripheralorgans [32 33] The distribution of receptors is organospe-cific Several types of binding sites may occur in the cells ofone organ MT

1receptors are predominant [1] Density and

affinity of receptors undergo significant changes during theday In the daytime when the concentration of melatonindecreases the number of its receptors is increasing [32 33]

31 Membrane Receptors MT1and MT

2 In the cells of vari-

ousmammalian species the two types ofmembrane receptorsare revealed MT

1and MT

2 formerly known as Mel

1a andMel1bMT

1is found in the hypothalamus the pituitary gland

cerebral cortex thalamus hippocampus cerebellum corneaand retina arteries heart lungs liver kidney adrenal glandskin and B and T lymphocytes [1 33 34] MT

2receptors are

localized in the hippocampus the cerebellum retina arteriesheart lungs liver small intestine and skin [1 32 35]

In humans the length of polypeptide chains is 350 and362 amino acids respectively MT

1and MT

2molecules

have high amino acid sequence homology (approximately60) [28] In accordance with the characteristics of theirspatial structure the MT

1MT2receptors belong to the

family of rhodopsin1205732-adrenergic receptors [36] They are

based on seven transmembrane 120572-helices connected by aseries of intra- and extracellular loops [34] The extracellularN-terminal fragment has the glycosylation sites and anintracellular C-terminal fragment includes phosphorylationsites [31 37] The palmitic acid residue can be attached to thecysteine residue of the fourth (intracellular) loop [38]

MT1and MT

2receptors have high affinity to melatonin

For molecules isolated from human cells 119870119889values are 807

and 383 pM respectively [39] Molecular mechanisms ofmelatonin binding to its receptors are far from sufficientlystudied It is assumed that the binding of 5-methoxyl groupof melatonin may involve residues of histidine (His195 in theMT1and His208 in the MT

2) and valine (Val-192) of the fifth

transmembrane helix The structure of pocket for bindingof melatoninrsquos N-acetyl group appears to differ for tworeceptors In the MT

1an important role belongs to the serine

residues (Ser110 and Ser114) in the third transmembranehelix whereas asparagine (Asn175) of the fourth helix hasgreater importance in the MT

2[28]

Recent works demonstrated polymorphisms of theMT1MT2receptors and related genes in human and animals

However these mutations did not have clear phenotypicexpression [28 40]

Membrane receptors are associated with G-protein how-ever depending on the tissue type intracellular signalingmechanisms may differ considerably The most commonis the suppression of cAMP synthesis by Gi-proteins bothsensitive and insensitive to pertussis toxin [34] This reduces

ISRN Biochemistry 3

the activity of protein kinase A and the phosphorylation ofseveral proteins For example it is shown that through recep-torsMT

1melatonin inhibits phosphorylation of transcription

factor CREB (cAMP response element binding) [41]The MT

1and MT

2receptors may be coupled with Gq11

protein which does not use cAMP-dependent pathway butphosphoinositide signaling The activation of phospholipaseC (isoforms 120573 and 120574) in cells leads to increased amount ofdiglycerides inositol trisphosphate and calcium ions andprotein kinaseC activation [34] Stimulation of protein kinaseC causes multiple effects including a cascade of mitogen-activated protein kinases (MAPKs) The phosphorylationwas experimentally determined for the following enzymesrelated to the cascade MEK1 andMEK2 JNK and ERK1 andERK2 With their activation the effect of melatonin on cellproliferation is linked [31 42] It is assumed that the activationof protein kinase C can be caused by the opening of calciumchannels dependent on G-protein and the action of 120573120574-dimers formed by separating of 120572i-subunit from G-protein[31]

Another potentially important mechanism of melatoninsignal transduction via the MT

2is the influence on the

level of cGMP While some researchers have observed anincrease in the number of cGMP probably due to inhibitionof phosphodiesterase [43] others found reduced activity ofsoluble guanylate cyclase and cGMP production [44]

Through the MT1and MT

2melatonin activates potas-

sium channels GIRK (G protein-coupled inwardly rectifyingpotassiumchannels) [45] andBKCa (large-conductanceCa

2+-activated K+ channels) The opening of potassium channelsmay underlie the vasomotor and neurotrophic effects ofepiphyseal hormone [31]

Molecules of MT1and MT

2as many receptors coupled

to G-proteins are capable of dimerization MT1homodimers

and MT1MT2heterodimers are formed in several times

lighter than homodimers MT2[46] Therefore it seems quite

possible to form heterodimers in the retina hippocampusand neurons of the suprachiasmatic nuclei in hypothalamuswhere both types of melatonin receptors are expressed Itis suggested that the formation of heterodimers may beimportant for the realization of the signal via the MT

2

receptors [32]Recent studies have shown that MT

1and MT

2form

complexes with certain intracellular proteins Some of themare associated with both receptors (filamin and IRS4 insulinreceptor substrate 4) while others show greater selectivityMT1receptor specifically interacts with phosphodiesterase

protein elongation factor EEF-1B120574 Rac1 (Ras-related C3botulinum toxin substrate 1) and Rap-1A (Ras-related pro-tein 1A) MT

2receptor binds to protein phosphatase 2C120574

(PP2C120574) and catenin 1205751 The biological role of this phe-nomenon is still unclear [32]

It is believed that modification of the affinity and numberof melatonin receptors is an important component of themechanism which regulates the circadian rhythm Prolongedexposure to hormone leads to desensitization of membranereceptors [47] probably as a result of phosphorylation ofthe C-terminus [38] Internalization of receptors occurs in

the usual manner The binding of MT1and MT

2with the

protein 120573-arrestin [48] facilitates interaction with clathrinadaptors which further leads to isolation of clathrin-coatedvesicle containing ldquoextrardquo receptors [49] After treatment withphysiological concentrations of hormone a long time (about8 hours) is required to restore the number of membranereceptors This process is largely dependent on the synthesisof new protein molecules [50]

32 Nuclear Receptors Nuclear receptors formelatonin RZRROR120572 and RZRROR120573 are also referred as NR1F1 and NR1F2according to the unified nomenclature They belong to afamily of the retinoid receptors and have lower affinityfor melatonin than MT

1and MT

2[31 51] RZRROR120572 is

localized mainly in the cerebellum thalamus hippocampuslymphocytes and skin while the RZRROR120573 is found in theretina pineal gland pituitary gland hypothalamus thalamusand spinal cord [51]

The nuclear receptors have a typical domain organizationC-terminal domain provides the ligand attaching It is alsoresponsible for receptor dimerization However unlike othermembers of the family of nuclear receptors RZRROR120572and RZRROR120573 can function as monomers DNA-bindingdomain composed of two ldquozinc fingersrdquo recognizes hexanu-cleotide RGGTCA (wherein R = A or G) adjacent to the 51015840-end to the AT rich sequences [52]

It is assumed that the nuclear melatonin receptors areresponsible for the manifestation of the hormone immuno-modulatory action as it enhances the syntheses of inter-leukins and 120574-interferon by T lymphocytes [53] In B lym-phocytes melatonin inhibits the formation of 5-lipoxygenasea key enzyme in the synthesis of leukotrienes which areinvolved in allergic and inflammatory response [54] Antipro-liferative effects of melatonin are also related with theactivation of nuclear receptors because specific hexanu-cleotides recognized by RZRROR were detected in thepromoters of some cell cycle regulatory proteins for examplep21WAF1CIP1 [51]

33 Melatonin Binding Sites

331 The Melatonin Binding Site GPR50 The polypeptidechain of this protein is 618 amino acid residues in lengthBinding site GPR50 has a high (about 45) amino acidsequence homology with MT

1and MT

2and structural

features specific for the melatonin receptors [55] GPR50was detected in the hypothalamus the pituitary gland hip-pocampus retina testes and kidneys [32] Despite the factthat GPR50 was cloned in 1996 its functions are still poorlyunderstood Recent studies have shown that GPR50 readilyforms heterodimers with receptors MT

1and MT

2 As part

of such heterodimers the MT2retains its properties while

the affinity of MT1to agonists dramatically reduced [32]

Association of MT1with GPR50 also prevents interaction

with G-protein and a 120573-arrestin that ultimately affects theintracellular signal transduction and internalisation of recep-tors [56]

4 ISRN Biochemistry

332 Melatonin Binding Site MT3 Discovery of this binding

site found in the liver kidney and brain [57] has generateda large number of still unsolved issues MT

3initially was

treated as a membrane receptor but later it turned out thatabout 90 of these molecules are localized in the cytoplasm[58] MT

3demonstrates low affinity to hormone 119870

119894value

is measured in nanomoles that exceeds the concentrationof melatonin in the blood With increasing temperature theaffinity decreases and to record the formation of complexMT3-2-(125I)-melatonin is practically impossible at 37∘C [57

58] Despite the efforts the mechanisms of signal transduc-tion from theMT

3have not been revealed yetThese findings

raise the validity of the MT3receptor as classical receptors

[59]As a result of numerous studies MT

3was identified as

quinone reductase QR2 (EC 110992) The biological role ofthe enzyme is unknown but it is assumed that it is involvedin neutralization of toxic quinones On this basis it has beenhypothesized that antioxidant properties of melatonin arerelated with the activity of QR2 [31]Method of X-ray analysisshows that melatonin attaches the enzyme not in allostericbut in the active center [60] In this case some researchersconsider a role of melatonin as a substrate electron donor inneutralization of active oxygen radicals [59] and the othersbelieve that it acts as competitive inhibitor of the enzyme[60] The data obtained with the help of nuclear magneticresonance confirm the second opinion [61]

4 Synthetic Ligands of Melatonin Receptors

41 Search Strategy of New Ligands In the past two decadesa large number of ligands for melatonin receptors havebeen synthesized Structure-activity relationships (SARs) ofmelatonin derivatives have been comprehensively analyzed[62ndash65] and we only summarize general strategies used inthe development of melatoninergic ligands

Large-scale search for effective melatonin receptor ago-nists was started in the late 80s The work was done on tissuesamples which contain as it turned out later a heteroge-neous set of melatonin binding sites so the dependence ofthe ldquostructure-activityrdquo was considered without taking intoaccount the differences in the structure of the receptor [65]The impetus for further research was the cloning of MT

1and

MT2and the selection of cell lines expressing only a certain

type of melatonin receptor (lines CHO COS-7 HEK293 andNIH3T3) [62] Retesting of known ligands on cell lines inmost cases showed their low selectivity for MT

1and MT

2 In

addition to traditional experimental methods the computersimulation of ligand is used more increasingly while theexisting algorithms do not allow distinguishing MT

1and

MT2[65]The formulas of some specific ligands of melatonin

receptors are given in Table 1First agonists were obtained bymodification ofmelatonin

structure These agonists were used to specify positionsimportant for interaction with the receptor Position 6 isdeterminative for binding as well as methoxy group (position5) and amide group of side chain Introduction into themolecule of large substituents in the positions 1 and 120573 leads

to dramatic decrease in affinity for the receptor In modi-fications of position 2 the biological activity is maintainedPotent agonists are molecules containing methyl phenyl orhalides in this position Radioactive form of 2-iodomelatonin(Table 1 structure 1) has become the standard for the studyof melatonin receptors [65] Bioisosteres were obtained byreplacement of nitrogen atom in the pyrrole ring by oxygenand sulfur [6] Shift of nitrogen from 1 to 3 positions appearsadmissible [73]

Positive results are shown for molecules with partialrestriction of conformational mobility [62] In such com-pounds indole rings are included in a system of three or fourconjugated cycles (structures 4 and 5) It was shown that theindole nucleusmay be substituted by other aromaticmoietiesOne of the most successful substitutions was a replacementof melatonin heterocycle by naphthalene (structures 8 and 9)[74] It was found that the presence of the ligand moleculeof condensed rings is not strictly necessary Good affinityappears in substances in which cycles are separated by shortlinear bridges [75] An interesting approach was used tocreate ldquodimericrdquo ligands a symmetric structures obtained byassociation of two molecules of known agonists (structure 10and 11) [70 76] Effective agonists occur among derivativesof indole benzofuran naphthalene and tetralin Work increation of novel agonists is still going on [77ndash82]

Search of selective agonists is essential for determinationof the role of each receptor type in the implementationof the biological effects of melatonin Although significantstructural similarity in MT

1and MT

2 in recent years

ligands were collected which specifically bind to one ofthese receptors For such a highly selective ligands the119870119894values are usually different in the tens or hundreds of

times (Table 1) There are cases where the influence of theligand on the functional activity of membrane receptors isopposite For example compound 5-HEAT (structure 2) isan agonist of MT

1and acts as an antagonist of MT

2[66]

The pharmacological profile of theMT3is very different from

the MT1and MT

2 The 5-MCA-NAT (structure 3) prazosin

and N-acetyltryptamine exhibit the highest selectivity [67]Specific ligand for the nuclear receptor is a thiazolidinedioneCGP52608 (structure 12) and structurally related molecules[83]

42 Prospects for Clinical Use of the Melatonin Receptors Ago-nists Currently onlymembranemelatonin receptor agonistshave clinical interest Although the number of synthesizedand tested ligands of MT

1MT2amounts to hundreds only

a few compounds have reached the stage of clinical trialsRamelteon (Rozerem) was developed by the pharmaceuticalcompany Takeda and approved in the US in 2005 Agome-latine (Valdoxan Melitor Thymanax) was developed by thepharmaceutical company Servier and approved in Europein 2009 Two melatonin agonists Tasimelteon and TIK-301have received orphan drug designation and are in clinicaltrials in the United States Tasimelteon was developed byVanda Pharmaceuticals and phase III of its clinical trialwas completed in 2010 TIK-301 was designed originally byEli Lilly and Company and since 2007 the trials have been

ISRN Biochemistry 5

Table 1 Synthetic ligands at melatonin receptors

Number Compoundlowast Type of ligand ReferenceMelatonin derivatives

1

NH

I

2-IodomelatoninK1i = 290pM

K2i = 250 pM

NHCOCH3

H3CO AgonistMT1 and MT2

[65]

2

NH

OHO

NHCOCH35-HEATK1i = 17nM

K2i = 76nM

Agonist MT1antagonist MT2

[66]

3

NH

HN

O NHCOCH3OCH3

K3i = 116pM

5MCA-NAT

Agonist MT3 [67]

Tri- and tetracyclic compounds

4

N

H3CO

NHCOC3H7

K-185K1i

K2i

= 89 Antagonist MT2[68]

5

N

H3CO

NHCOC3H7

IIK7K1i

K2i

= 89Agonist MT2

[68]

6O

NHCOC2H5 RamelteonK1i = 14pM

K2i = 45pM Agonist

MT1 and MT2

[65]

7

O

NHCOC2H5

TasimelteonK1i = 35 pM

K2i = 17pM

AgonistMT1 and MT2

[30]

6 ISRN Biochemistry

Table 1 Continued

Number Compoundlowast Type of ligand ReferenceNaphthalene and tetralin analogues

8

NHCOCH3

H3CO K1i = 62pM

K2i = 268pM

AgomelatineAgonist

MT1 and MT2

[69]

9

NHCOC2H5

K1i

K2i

= 126

4P-PDOT

Antagonist MT2 [70]

ldquoDimeric ligandsrdquo

10K2i

K1i

= 121

NHCOCH3

H3CCONH

Agonist MT1[70]

11 O O

NHCOCH3 H3CCONH

K2i

K1i

= 224

S26131

Antagonist MT1 [71]

Thiazolidine analogues

12 N

S

NNHNH

S

O

H2C

CH3 CGP 52608KRi = 484nM

Agonist RZRROR [72]

lowastFor ligands with low selectivity to theMT1 andMT2 and also for theMT3 and RZRROR ligands the values of the dissociation constants for receptor complexare shown as1198701

11989411987021198941198703119894119870119877119894 respectively For ligands of high selectivity the ratios of the dissociation constants are given1198701

1198941198702

119894or11987021198941198701

119894

undergone in Tikvah Pharmaceuticals In February 2013Neurim Pharmaceuticals reported positive results of phase IIof trials for piromelatine (Neu-P11)

Ramelteon N-2-[(8S)-1678-tetrahydro-2H-indeno[54-b]furan-8-yl]ethyl propanamide is the first amongthe melatonin receptor agonists approved by FDA Theaffinity of ramelteon for MT

1and MT

2exceeds the affinity

of the natural ligand (Table 1) and so in cell culturesramelteon demonstrates better result in the inhibition offorskolin-induced synthesis of cAMP Significance of IC50(half maximal inhibitory concentration) of ramelteon andmelatonin varies in 3ndash18 times depending on the type ofreceptor [39]

When orally administered ramelteon is rapidly absorbedPeak of drug concentration in plasma is achieved in

approximately 1 h after administration [84] The drug ismetabolized in the liver by hydroxylation and subsequentconjugation with glucuronic acid [85] To date 4 metabolitesare identified It was found that the major metabolite (M-II) hydroxylated at position C2 of propionyl residue is weakagonist of MT

1MT2receptor Its elimination half-life is from

2 to 5 hours According to some estimates which take intoaccount the duration of the metabolite existence half-life oframelteon may reach 26 hours [86] The existence of a long-lived activemetabolite should contribute to themanifestationof the pharmacological effects of ramelteon that should beconsidered as a decisive advantage for the use of the drug inclinical practice

During the preclinical and clinical trials it was shown thatramelteon promotes sleep without causing any significant

ISRN Biochemistry 7

side effects The drug does not affect the coordination ofmovements memory and learning ability It has no sedativeeffect so sleep induced by the drug is indistinguishable fromnatural sleep [87] It appears that the absence of undesir-able side effects of ramelteon is explained by inability tobind receptors of benzodiazepine dopamine serotonin andopioids [88] Ramelteon reduces sleep latency and increasestotal sleep time without causing hangover addiction andwithdrawal effects [87]

Due to proven clinical effectiveness and safety ramelteonis considered as the fourth-generation drug for the treatmentof primary insomnia and insomnia associated with circadianrhythms [89] Other possible fields of ramelteon applicationrequire a detailed study More detailed information on theresults of preclinical and clinical testing can be found in thereviews [87 89 90]

Agomelatine N-[2-(7-Methoxy-1-naphthyl)ethyl] is aderivative of naphthalene The drug has a high affinity toMT1MT2receptors comparable with melatonin (Table 1)

When administered per os agomelatine as well asramelteon has low bioavailability Peak of drug concentrationin blood plasma is observed within 1-2 hours Almost allof the molecules of agomelatine are associated with bloodproteins Biotransformation of agomelatine occurs mainly inthe liver to form hydroxylated and demethylated derivativesFour metabolites of agomelatine are identified 3-hydroxy-7-methoxy- 7-desmethyl- and dihydrodiol-agomelatine [91]These compounds are not biologically active and are excretedin the urine Half-life is less than 2 hours [89]

Binding to MT1MT2receptors agomelatine synchro-

nizes circadian rhythms in animals with delayed sleep phasesyndrome [86] In clinical trials agomelatine also demon-strates positive phase shifting properties it induces a phaseadvance of sleep body temperature decline and melatoninonset [86] Agomelatine is a selective antagonist of theserotonin receptors 5-HT

2C [92] Because of this peculiaritythe drug can be used for the treatment of depressive disorders[93ndash95] Therefore agomelatine is a unique tool againstinsomnia caused by depression A detailed review of thepharmacological properties of the drug can be found in theliterature [89 95 96]

Tasimelteon (VEC-162 BMS-214778) is a derivativeof propanamide N-[[(1R 2R)-2-(23-dihydro-1-benzofuran-4-yl)cyclopropyl]methyl] propanamide The drug demon-strates a higher affinity for melatonin receptors than naturalligand (Table 1) Unlike melatonin ramelteon and agomela-tine binding of MT

2is easier than MT

1[30]

In plasma tasimelteon circulates predominantly inprotein-bound form (lt91)Thedrug is distributed through-out the body Its metabolism occurs in the liver by hydroxy-lation and dehydrogenation [97]

In clinical trials tasimelteon improved sleep latency sleepefficiency andwake after sleep onset (ie sleepmaintenance)The drug exhibits a good safety profile with no significant sideeffects in comparison with placebo [98] On May 31 2013Vanda Pharmaceuticals Inc presented tasimelteon as a newdrug for the treatment of Non-24-hour sleep-wake disorder

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 [99] Neu-P11 is alsoagonist of melatonin receptors MT

1MT2and serotonin

receptors 5-HT1A1D and so has the properties which are

weakly expressed in other melatoninergic drugs Neu-P11has antidepressant and anxiolytic properties similar tothose of melatonin [100] It appears that preparation willfind application in the treatment of affective disordersNeu-P11 is able to attenuate cognitive impairment that maybe promising in the treatment of Alzheimerrsquos disease [101]In addition positive effects of Neu-P11 on glucose level andtriglycerides by increasing the sensitivity of cells to insulinare shown [102]

5 Conclusion

After half a century of studying melatonin it is consideredas an integral part of the homeostatic mechanisms of theorganism and a hormone involved in regulating a largenumber of various physiological processes Definition of themelatonin receptors structure the discovery of signalingmechanisms the establishment of cell lines and animal mod-els and synthesizing onlyMT

1orMT

2 all this contributed to

the understanding of the role ofmelatonin and its receptors inthe modulation of visual circadian endocrine and immunefunctions

The accumulated information served as a catalyst forthe creation of synthetic melatonergic ligands Over the pastthree decades there were synthesized and tested hundredsof molecules which specifically bind to melatonin receptorsFunctional groups ofmelatonin which are critical for bindingto the receptors have been clarified that allowed a realizationof the systematic approach to the synthesis of new ligandsRadiolabeled ligands selective agonists and antagonists toMT1andMT

2receptors were already used as a tool for study-

ing of melatonin functioning Some melatonin agonists haveobvious pharmacological value Currently five compounds(ramelteon agomelatine tasimelteon Neu-P11 and TIK-301)have reached a stage of clinical trials two of them (ramelteonand agomelatine) gained approval for clinical use as drugsfor the treatment of insomnia and violations of circadianrhythms

However the development of the new melatoninergicligands is far from complete It is necessary to expand thespectrum of high-selective agonists and antagonists whichcould be used both for scientific research and in medicalpractice It seems to be promising a study of synergistic rela-tionships between melatonin receptors and receptor of neu-rotransmitters such as serotonin This dual activity detectedin agomelatine made it effective in treatment of insomniacaused by depression Another important direction is thesearch of melatonergic ligands with other pharmacologicalactivities Based on the biological role of melatonin amongits ligands we can expect the existence of potential drugsfor treatment of oncological diseases and metabolic andendocrine disorders

8 ISRN Biochemistry

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

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[1] B Zawilska D J Skene and J Arendt ldquoPhysiology andpharmacology of melatonin in relation to biological rhythmsrdquoPharmacological Reports vol 61 no 3 pp 383ndash410 2009

[2] R Hardeland ldquoNeurobiology pathophysiology and treatmentof melatonin deficiency and dysfunctionrdquo The Scientific WorldJournal vol 2012 Article ID 640389 18 pages 2012

[3] M A Q Salva and S Hartley ldquoMood disorders ircadianrhythms melatonin and melatonin agonistsrdquo Journal of CentralNervous System Disease vol 4 pp 15ndash26 2012

[4] V Srinivasan R Zakaria H J Singh andDAcuna-CastroviejoldquoMelatonin and its agonists in pain modulation and its clinicalapplicationrdquo Archives Italiennes de Biologie vol 150 no 4 pp274ndash289 2012

[5] A Carpentieri G D de Barboza V Areco M P Lopez andN T de Talamoni ldquoNew perspectives in melatonin usesrdquo Phar-macological Research vol 65 no 4 pp 437ndash444 2012

[6] GMBrown S R Pandi-Perumal I Trakht andD PCardinalildquoMelatonin and its relevance to jet lagrdquo Travel Medicine andInfectious Disease vol 7 no 2 pp 69ndash81 2009

[7] G Escames and D Acuna-Castroviejo ldquoMelatonin syntheticanalogs and the sleepwake rhythmrdquo Revue Neurologique vol48 no 5 pp 245ndash254 2009

[8] R Hardeland ldquoChronobiology of melatonin beyond the feed-back to the suprachiasmatic nucleusmdashconsequences to mela-tonin dysfunctionrdquo International Journal of Molecular Sciencesvol 14 no 3 pp 5817ndash5841 2013

[9] V Srinivasan S R Pandi-Perumal I Trakht et al ldquoPathophysi-ology of depression role of sleep and the melatonergic systemrdquoPsychiatry Research vol 165 no 3 pp 201ndash214 2009

[10] M D Maldonado M A Perez-San-Gregorio and R J ReiterldquoThe role of melatonin in the immuno-neuro-psychology ofmental disordersrdquo Recent Patents on CNS Drug Discovery vol4 no 1 pp 61ndash69 2009

[11] E B Arushanian and L G Arushanian ldquoPineal melatonin asan anti-stress agentrdquoEksperimentalrsquonaia i Klinicheskaia Farmak-ologiia vol 60 no 6 pp 71ndash77 1997 (Russian)

[12] R Konakchieva Y Mitev O F Almeida and V K PatchevldquoChronic melatonin treatment and the hypathalamo-pituitary-adrenal axis in the rat attenuation of the secretory response tostress and effects on hypothalamic neuropeptide content andreleaserdquo Biology of the Cell vol 89 no 9 pp 587ndash596 1997

[13] R J Reiter D-X Tan L C Manchester S D Paredes J CMayo and RM Sainz ldquoMelatonin and reproduction revisitedrdquoBiology of Reproduction vol 81 no 3 pp 445ndash456 2009

[14] G Petrosillo G Colantuono N Moro et al ldquoMelatoninprotects against heart ischemia-reperfusion injury by inhibitingmitochondrial permeability transition pore openingrdquoAmericanJournal of Physiology vol 297 no 4 pp H1487ndashH1493 2009

[15] R J Reiter D-X Tan and A Korkmaz ldquoThe circadian mela-tonin rhythm and its modulation possible impact on hyperten-sionrdquo Journal of Hypertension vol 27 no 6 pp S17ndashS20 2009

[16] D P Cardinali A I Esquifino V Srinivasan and S RPandi-Perumal ldquoMelatonin and the immune system in agingrdquoNeuroImmunoModulation vol 15 no 4ndash6 pp 272ndash278 2008

[17] V Srinivasan D W Spence I Trakht S R Pandi-PerumalD P Cardinali and G J Maestroni ldquoImmunomodulation bymelatonin its significance for seasonally occurring diseasesrdquoNeuroImmunoModulation vol 15 no 2 pp 93ndash101 2008

[18] V Srinivasan DW Spence S R Pandi-Perumal I Trakht andD P Cardinali ldquoTherapeutic actions of melatonin in cancerpossible mechanismsrdquo Integrative Cancer Therapies vol 7 no3 pp 189ndash203 2008

[19] R Santoro F Mori M Marani et al ldquoBlockage of melatoninreceptors impairs p53-mediated prevention of DNA damageaccumulationrdquoCarcinogenesis vol 34 no 5 pp 1051ndash1061 2013

[20] A Korkmaz T Topal D-X Tan and R J Reiter ldquoRole ofmelatonin in metabolic regulationrdquo Reviews in Endocrine andMetabolic Disorders vol 10 no 4 pp 261ndash270 2009

[21] A Karamitri N Renault N Clement J L Guillaume andR Jockers ldquoMinireview toward the establishment of a linkbetween melatonin and glucose homeostasis association ofmelatonin MT

2receptor variants with type 2 diabetesrdquoMolecu-

lar Endocrinology vol 27 no 8 pp 1217ndash1233 2013[22] V L Kozeltsev T V Volodina V V Guseva and N V Kostyk

ldquoCharacteristics of changes in lipids of granulation fibrous tissueof rats subjected to different doses and modes of melatoninadministrationrdquo Biochemistry B vol 1 no 3 pp 220ndash224 2007

[23] N V Kostiuk V V Zhigulina M B Belyakova et al ldquoEffectof melatonin on lipid barrier in ratsrsquo skinrdquo American Journal ofBiochemistry vol 2 no 5 pp 67ndash73 2012

[24] D C Klein ldquoArylalkylamine N-acetyltransferase lsquothe timez-ymersquordquo Journal of Biological Chemistry vol 282 no 7 pp 4233ndash4237 2007

[25] J Falcon L Besseau M Fuentes S Sauzet E Magnanouand G Boeuf ldquoStructural and functional evolution of thepineal melatonin system in vertebratesrdquo Annals of the New YorkAcademy of Sciences vol 1163 pp 101ndash111 2009

[26] R Hardeland ldquoMelatonin hormone of darkness and moreoccurrence controlmechanisms actions and bioactivemetabo-litesrdquo Cellular and Molecular Life Sciences vol 65 no 13 pp2001ndash2018 2008

[27] T A Bedrosian K L Herring J CWalton L K Fonken Z MWeil and R J Nelson ldquoEvidence for feedback control of pinealmelatonin secretionrdquoNeuroscience Letters vol 542 pp 123ndash1252013

[28] M L Dubocovich P Delagrange D N Krause D SugdenD P Cardinali and J Olcese ldquoInternational union of basicand clinical pharmacology LXXVNomenclature classificationand pharmacology of G protein-coupled melatonin receptorsrdquoPharmacological Reviews vol 62 no 3 pp 343ndash380 2010

[29] R Hardeland S R Pandi-Perumal and D P Cardinali ldquoMela-toninrdquo International Journal of Biochemistry and Cell Biologyvol 38 no 3 pp 313ndash316 2006

[30] R Hardeland ldquoNew approaches in the management of insom-nia weighing the advantages of prolonged-release melatoninand synthetic melatoninergic agonistsrdquo Neuropsychiatric Dis-ease and Treatment vol 5 no 1 pp 341ndash354 2009

[31] R Hardeland ldquoMelatonin signaling mechanisms of a plei-otropic agentrdquo BioFactors vol 35 no 2 pp 183ndash192 2009

[32] R Jockers P Maurice J A Boutin and P Delagrange ldquoMela-tonin receptors heterodimerization signal transduction andbinding sites whatrsquos newrdquo British Journal of Pharmacology vol154 no 6 pp 1182ndash1195 2008

[33] C Gall J H Stehle and D R Weaver ldquoMammalian melatoninreceptors molecular biology and signal transductionrdquo Cell andTissue Research vol 309 no 1 pp 151ndash162 2002

ISRN Biochemistry 9

[34] M L Dubocovich M A Rivera-Bermudez M J Gerdinand M I Masana ldquoMolecular pharmacology regulation andfunction of mammalian melatonin receptorsrdquo Frontiers inBioscience vol 8 pp 1093ndash1108 2003

[35] NV Kostiuk V V ZhigulinaM B Belyakova D V Leschenkoand M V Minyaev ldquoMelatonin receptors and their agonistsrdquoProblems of Biological Medical and Pharmaceutical Chemistryvol 5 pp 49ndash58 2011

[36] X Deupi N Dolker M L Lopez-Rodrıguez M Campillo JA Ballesteros and L Pardo ldquoStructural models of class a Gprotein-coupled receptors as a tool for drug design insights ontransmembrane bundle plasticityrdquo Current Topics in MedicinalChemistry vol 7 no 10 pp 991ndash998 2007

[37] M L Dubocovich and M Markowska ldquoFunctional MT1and

MT2melatonin receptors in mammalsrdquo Endocrine vol 27 no

2 pp 101ndash110 2005[38] S Sethi W Adams J Pollock and P A Witt-Enderby ldquoC-

terminal domains within human MT1and MT

2melatonin

receptors are involved in internalization processesrdquo Journal ofPineal Research vol 45 no 2 pp 212ndash218 2008

[39] K Kato K Hirai K Nishiyama et al ldquoNeurochemical prop-erties of ramelteon (TAK-375) a selective MT

1MT2receptor

agonistrdquo Neuropharmacology vol 48 no 2 pp 301ndash310 2005[40] P Lai B Y Zhang PWang M X ChuW J Song and B J Cai

ldquoPolymorphism of the melatonin receptor genes and its rela-tionshipwith seasonal reproduction in the gulinma goat breedrdquoReproduction in Domestic Animals vol 48 no 5 pp 732ndash7372013

[41] S McNulty A W Ross K Y Shiu P J Morgan and M HHastings ldquoPhosphorylation of CREB in ovine pars tuberalisis regulated both by cyclic AMP-dependent and cyclic AMP-independent mechanismsrdquo Journal of Neuroendocrinology vol8 no 8 pp 635ndash645 1996

[42] A S Chan F P Lai R K Lo T A Voyno-Yasenetskaya E JStanbridge and YHWong ldquoMelatoninmt

1andMT

2receptors

stimulate c-Jun N-terminal kinase via pertussis toxin-sensitiveand-insensitive G proteinsrdquoCellular Signalling vol 14 no 3 pp249ndash257 2002

[43] S R Pandi-Perumal I Trakht V Srinivasan et al ldquoPhysiolog-ical effects of melatonin role of melatonin receptors and signaltransduction pathwaysrdquo Progress in Neurobiology vol 85 no 3pp 335ndash353 2008

[44] L Petit I Lacroix P Coppet A D Strosberg and R JockersldquoDifferential signaling of human Mel1a and Mel1b melatoninreceptors through the cyclic guanosine 31015840-51015840-monophosphatepathwayrdquo Biochemical Pharmacology vol 58 no 4 pp 633ndash6391999

[45] C S Nelson J LMarino and C N Allen ldquoMelatonin receptorsactivate heteromeric G-protein coupled Kir3 channelsrdquo Neu-roReport vol 7 no 3 pp 717ndash720 1996

[46] M A Ayoub A Levoye P Delagrange and R Jockers ldquoPrefer-ential formation ofMT

1MT2melatonin receptor heterodimers

with distinct ligand interaction properties compared with MT2

homodimersrdquo Molecular Pharmacology vol 66 no 2 pp 312ndash321 2004

[47] T Kokkola M Vaittinen and J T Laitinen ldquoInverse agonistexposure enhances ligand binding and G protein activation ofthe humanMT

1melatonin receptor but leads to receptor down-

regulationrdquo Journal of Pineal Research vol 43 no 3 pp 255ndash262 2007

[48] CD Bondi RMMcKeon JM Bennett et al ldquoMT1melatonin

receptor internalization underlies melatonin-induced morpho-logic changes in Chinese hamster ovary cells and these pro-cesses are dependent on Gi proteins MEK 12 and microtubulemodulationrdquo Journal of Pineal Research vol 44 no 3 pp 288ndash298 2008

[49] L M Luttrell and R J Lefkowitz ldquoThe role of 120573-arrestins in thetermination and transduction of G-protein-coupled receptorsignalsrdquo Journal of Cell Science vol 115 no 3 pp 455ndash465 2002

[50] M J Gerdin M I Masana M A Rivera-Bermudez et alldquoMelatonin desensitizes endogenous MT

2melatonin receptors

in the rat suprachiasmatic nucleus relevance for defining theperiods of sensitivity of the mammalian circadian clock tomelatoninrdquo The FASEB Journal vol 18 no 14 pp 1646ndash16562004

[51] C Carlberg ldquoGene regulation by melatoninrdquo Annals of the NewYork Academy of Sciences vol 917 pp 387ndash396 2000

[52] V Giguere M Tini G Flock E Ong R M Evans and G Otu-lakowski ldquoIsoform-specific amino-terminal domains dictateDNA-binding properties of ROR120572 a novel family of orphanhormone nuclear receptorsrdquo Genes amp Development vol 8 no5 pp 538ndash553 1994

[53] G J M Maestroni ldquoThe immunoneuroendocrine role of mela-toninrdquo Journal of Pineal Research vol 14 pp 1ndash10 1993

[54] D Steinhilber M Brungs O Werz et al ldquoThe nuclear receptorfor melatonin represses 5-lipoxygenase gene expression inhumanB lymphocytesrdquo Journal of Biological Chemistry vol 270no 13 pp 7037ndash7040 1995

[55] S M Reppert D R Weaver T Ebisawa C D Mahle and L FKolakowski Jr ldquoCloning of a melatonin-related receptor fromhuman pituitaryrdquo FEBS Letters vol 386 no 2-3 pp 219ndash2241996

[56] A Levoye J Dam M A Ayoub et al ldquoThe orphan GPR50receptor specifically inhibits MT

1melatonin receptor function

through heterodimerizationrdquoTheEMBO Journal vol 25 no 13pp 3012ndash3023 2006

[57] O Nosjean J-P Nicolas F Klupsch P Delagrange E Canetand J A Boutin ldquoComparative pharmacological studies ofmelatonin receptors mt1 mt2 and mt3qr2 tissue distributionofmt3qr2rdquo Biochemical Pharmacology vol 61 no 11 pp 1369ndash1379 2001

[58] F Mailliet G Ferry F Vella et al ldquoCharacterization of themelatoninergicMT

3binding site on theNRH quinone oxidore-

ductase 2 enzymerdquo Biochemical Pharmacology vol 71 no 1-2pp 74ndash88 2005

[59] D-X Tan L C Manchester M P Terron L J Flores HTamura and R J Reiter ldquoMelatonin as a naturally occurring co-substrate of quinone reductase-2 the putative MT

3melatonin

membrane receptor hypothesis and significancerdquo Journal ofPineal Research vol 43 no 4 pp 317ndash320 2007

[60] B Calamini B D Santarsiero J A Boutin and A D MesecarldquoKinetic thermodynamic and X-ray structural insights into theinteraction of melatonin and analogues with quinone reductase2rdquo Biochemical Journal vol 413 no 1 pp 81ndash91 2008

[61] J A Boutin E Marcheteau P Hennig et al ldquoMT3QR2melatonin binding site does not use melatonin as a substrateor a co-substraterdquo Journal of Pineal Research vol 45 no 4 pp524ndash531 2008

[62] D P Zlotos ldquoRecent advances in melatonin receptor ligandsrdquoArchiv der Pharmazie vol 338 no 5-6 pp 229ndash247 2005

[63] P A Witt-Enderby and P-K Li ldquoMelatonin receptors andligandsrdquo Vitamins and Hormones vol 58 pp 321ndash354 2000

10 ISRN Biochemistry

[64] D Steinhilberg and C Carlberg ldquoMelatonin receptor ligandsrdquoExpert Opinion onTherapeutic Patents vol 9 no 3 pp 281ndash2901999

[65] S Rivara M Mor A Bedini G Spadoni and G Tarzia ldquoMela-tonin receptor agonists SAR and applications to the treatmentof sleep-wake disordersrdquoCurrent Topics inMedicinal Chemistryvol 8 no 11 pp 954ndash968 2008

[66] R Nonno V Lucini G Spadoni et al ldquoA newmelatonin recep-tor ligand with mt

1-agonist and MT

2-antagonist propertiesrdquo

Journal of Pineal Research vol 29 no 4 pp 234ndash240 2000

[67] E J Molinari P C North and M L Dubocovich ldquo2-[125I]Iodo-5-methoxycarbonylamino-N-acetyltryptamine aselective radioligand for the characterization of melatonin ML

2

binding sitesrdquo European Journal of Pharmacology vol 301 no1ndash3 pp 159ndash168 1996

[68] R Faust P J Garratt R Jones et al ldquoMapping the melatoninreceptor 6 Melatonin agonists and antagonists derived from6H-isoindolo[21-a]indoles 56-dihydroindolo[21-a]isoquin-olines and 67-dihydro-5H-benzo[c]azepino[21-a]indolesrdquoJournal of Medicinal Chemistry vol 43 no 6 pp 1050ndash10612000

[69] M J Millan A Gobert F Lejeune et al ldquoThe novel mela-tonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors blockade of which enhancesthe activity of frontocortical dopaminergic and adrenergicpathwaysrdquo Journal of Pharmacology and Experimental Thera-peutics vol 306 no 3 pp 954ndash964 2003

[70] V Audinot F Mailliet C Lahaye-Brasseur et al ldquoNew selectiveligands of human cloned melatonin MT

1and MT

2receptorsrdquo

Naunyn-Schmiedebergrsquos Archives of Pharmacology vol 367 no6 pp 553ndash561 2003

[71] C Descamps-Francois S Yous P Chavatte et al ldquoDesign andsynthesis of naphthalenic dimers as selective MT

1melatoniner-

gic ligandsrdquo Journal of Medicinal Chemistry vol 46 no 7 pp1127ndash1129 2003

[72] I Wiesenberg M Missbach J-P Kahlen M Schrader and CCarlberg ldquoTranscriptional activation of the nuclear receptorRZR120572 by the pineal gland hormone melatonin and identifica-tion of CGP 52608 as a synthetic ligandrdquoNucleic Acids Researchvol 23 no 3 pp 327ndash333 1995

[73] G Tarzia G Diamantini B Giacomo et al ldquo1-(2-alkanami-doethyl)-6-methoxyindole derivatives a new class of potentindole melatonin analoguesrdquo Journal of Medicinal Chemistryvol 40 no 13 pp 2003ndash2010 1997

[74] S Yous J Andrieux H E Howell et al ldquoNovel naphthalenicligands with high affinity for the melatonin receptorrdquo Journal ofMedicinal Chemistry vol 35 no 8 pp 1484ndash1486 1992

[75] J R Epperson J A Deskus A J Gentile L G Iben E Ryanand N S Sarbin ldquo4-Substituted anilides as selective melatoninMT2receptor agonistsrdquo Bioorganic amp Medicinal Chemistry

Letters vol 14 no 4 pp 1023ndash1026 2004

[76] B Giacomo A Bedini G Spadoni et al ldquoSynthesis and biolog-ical activity of new melatonin dimeric derivativesrdquo Bioorganicamp Medicinal Chemistry vol 15 no 13 pp 4643ndash4650 2007

[77] K H Chan Y HuM KHo and YHWong ldquoCharacterizationof substituted phenylpropylamides as highly selective agonistsat the melatonin MT

2receptorrdquo Current Medicinal Chemistr

vol 20 no 2 pp 289ndash300 2013

[78] S Rivara D Pala A Lodola et al ldquoMT1-selective mela-

tonin receptor ligands synthesis pharmacological evalua-tion and molecular dynamics investigation of N-[(3-O-sub-stituted)anilino]alkylamidesrdquo ChemMedChem vol 7 no 11pp 1954ndash1964 2012

[79] Y Hu M K Ho K H Chan D C New and Y H Wong ldquoSyn-thesis of substitutedN-[3-(3-methoxyphenyl)propyl] amides ashighly potent MT

2-selective melatonin ligandsrdquo Bioorganic amp

Medicinal Chemistry Letters vol 20 no 8 pp 2582ndash2585 2010[80] A Carocci A Catalano A Lovece et al ldquoDesign synthesis

and pharmacological effects of structurally simple ligands forMT1and MT

2melatonin receptorsrdquo Bioorganic amp Medicinal

Chemistry vol 18 no 17 pp 6496ndash6511 2010[81] L Morellato G M Lefas-Le M Langlois et al ldquoSyn-

thesis of newN-(arylcyclopropyl)acetamides andN-(arylvinyl)acetamides as conformationally-restricted ligands for mela-tonin receptorsrdquo Bioorganic ampMedicinal Chemistry Letters vol23 no 2 pp 430ndash434 2013

[82] G Li H Zhou Y Jiang et al ldquoDesign and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl- cyclopropanecarboxamide derivatives as novel melatonin receptor ligandsrdquoBioorganic amp Medicinal Chemistry Letters vol 21 no 4 pp1236ndash1242 2011

[83] M Missbach B Jagher I Sigg S Nayeri G Carlberg andI Wiesenberg ldquoThiazolidine diones specific ligands of thenuclear receptor retinoid Z receptorretinoid acid receptor-related orphan receptor 120572 with potent antiarthritic activityrdquoJournal of Biological Chemistry vol 271 no 23 pp 13515ndash135221996

[84] A Vermeeren ldquoResidual effects of hypnotics epidemiology andclinical implicationsrdquo CNS Drugs vol 18 no 5 pp 297ndash3282004

[85] J Wagner and M L Wagner ldquoNon-benzodiazepines for thetreatment of insomniardquo Sleep Medicine Reviews vol 4 no 6pp 551ndash581 2000

[86] KDoghramji ldquoMelatonin and its receptors a new class of sleep-promoting agentsrdquo Journal of Clinical Sleep Medicine vol 3 no5 pp S17ndashS23 2007

[87] M Miyamoto ldquoPharmacology of ramelteon a selectiveMT1MT2receptor agonist a novel therapeutic drug for sleep

disordersrdquo CNS Neuroscience amp Therapeutics vol 15 no 1 pp32ndash51 2009

[88] RH Farber and P J Burke ldquoPost-bedtime dosingwith indiplonin adults and the elderly results from two placebo-controlledactive comparator crossover studies in healthy volunteersrdquoCurrent Medical Research and Opinion vol 24 no 3 pp 837ndash846 2008

[89] V Srinivasan D P Cardinali S Pandi-Perumal and G BrownldquoMelatonin agonists for treatment of sleep and depressivedisordersrdquo Journal of Experimental and Integrative Medicinevol 1 no 3 pp 149ndash158 2011

[90] S R Pandi-Perumal V Srinivasan D W Spence et al ldquoRam-elteon a review of its therapeutic potential in sleep disordersrdquoAdvances in Therapy vol 26 no 6 pp 613ndash626 2009

[91] J J Bogaards E M Hissink M Briggs et al ldquoPrediction ofinterindividual variation in drug plasma levels in vivo fromindividual enzyme kinetic data and physiologically based phar-macokinetic modelingrdquo European Journal of PharmaceuticalSciences vol 12 no 2 pp 117ndash124 2000

[92] G Racagni M A Riva R Molteni et al ldquoMode of actionof agomelatine synergy between melatonergic and 5-HT2C

ISRN Biochemistry 11

receptorsrdquo World Journal of Biological Psychiatry vol 12 no 8pp 574ndash587 2011

[93] D de Berardis G di Iorio T Acciavatti et al ldquoThe emergingrole of melatonin agonists in the treatment of major depressionfocus on agomelatinerdquo CNS amp Neurological Disorders DrugTargets vol 10 no 1 pp 119ndash132 2011

[94] C de Bodinat B Guardiola-Lemaitre E Mocaer P Renard CMunoz and M J Millan ldquoAgomelatine the first melatonergicantidepressant discovery characterization and developmentrdquoNature Reviews Drug Discovery vol 9 no 8 pp 628ndash642 2010

[95] V Srinivasan R Zakaria Z Othman E C Lauterbach andD Acuna-Castroviejo ldquoAgomelatine in depressive disorders itsnovel mechanisms of actionrdquo Journal of Neuropsychiatry andClinical Neurosciences vol 24 no 3 pp 290ndash308 2012

[96] K Demyttenaere ldquoAgomelatine a narrative reviewrdquo EuropeanNeuropsychopharmacology vol 21 no 4 pp S703ndashS709 2011

[97] N N Vachharajani K Yeleswaram and D W Boulton ldquoPre-clinical pharmacokinetics and metabolism of BMS-214778 anovel melatonin receptor agonistrdquo Journal of PharmaceuticalSciences vol 92 no 4 pp 760ndash772 2003

[98] S M W Rajaratnam M H Polymeropoulos D M Fisheret al ldquoMelatonin agonist tasimelteon (VEC-162) for transientinsomnia after sleep-time shift two randomised controlledmulticentre trialsrdquo The Lancet vol 373 no 9662 pp 482ndash4912009

[99] G Spadoni A Bedini S Rivara and M Mor ldquoMelatoninreceptor agonists new options for insomnia and depressiontreatmentrdquo CNS Neuroscience amp Therapeutics vol 17 no 6 pp733ndash741 2011

[100] S TianM Laudon LHan et al ldquoAntidepressant-and anxiolyticeffects of the novel melatonin agonist Neu-P11 in rodentmodelsrdquo Acta Pharmacologica Sinica vol 31 no 7 pp 775ndash7832010

[101] PHe XOuyang S Zhou et al ldquoAnovelmelatonin agonistNeu-P11 facilitates memory performance and improves cognitiveimpairment in a rat model of Alzheimerrsquo diseaserdquo Hormonesand Behavior vol 64 no 1 pp 1ndash7 2013

[102] P P Wang M H She P P He et al ldquoPiromelatine decreasestriglyceride accumulation in insulin resistant 3T3-L1 adipo-cytes role of ATGL andHSLrdquoBiochimie vol 95 no 8 pp 1650ndash1654 2013

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology

2 ISRN Biochemistry

1

2

34

5

6

7

NH

NH

O

120573 CH3

H3CO

Figure 1 Structure of melatonin

mechanism of regulation of the gland synthetic activityprovides a circadian rhythm of melatonin secretion with apeak at night period [1 25] It was found that the effect ofneurotransmitter is associated with increased transport oftryptophan in pinealocytes formation of the terminal synthe-sizing enzyme hydroxy-O-methyltransferase and activationof serotonin acetylation with simultaneous suppression of itsoxidative deamination [26] Synthesis ofmelatonin is affectedby dopamine glutamate GABA and serotonin These com-pounds alter the activity of serotonin-N-acetyltransferaseExogenous melatonin can also modulate the synthesis byboth inhibiting and stimulating it [26 27]

Epiphysis is not the only organ secreting melatonin Cellsproducing this indole are found in the retina Harderiangland gastrointestinal tract pancreas respiratory tract andthyroid and adrenal glands [26 27] Some scientists believethat extrapineal sources account for less than 20 of thebodyrsquos melatonin and others consider enterochromaffin cellsas the main source of the hormone [26]

Newly synthesized melatonin is not accumulated inendocrine cells It leaves the place of synthesis easily becauseof its ability to passively diffuse through the cellmembrane Inblood melatonin binds to proteins preferably with a serumalbumin and acidic glycoprotein 1205721 [28]

23 Degradation of Melatonin As some compounds ofindole nature melatonin has a short half-life (30ndash50 min-utes depending on the species) In the liver biotransfor-mation is carried out by hydroxylation and subsequentformation of conjugates with sulfuric and glucuronic acidsIn the other organs the hormone metabolism proceedsotherwise The most common is deacetylation to forma 5-methoxytryptamine In the retina this compound isconverted into 5-methoxyindoleacetic acid and 5-methox-ytryptophol [29] Mononuclear leukocytes are capable ofregenerating N-acetyl serotonin and serotonin from mela-tonin [29] While in brain cells the opening of melatoninpyrrole ring leads to formation of kynuramines [26] Productsof degradation are mostly excreted with the urine Studiesconcerning the exchange of melatonin are reviewed fully[25 28 30]

3 Melatonin Receptors

In recent times a number of melatonin receptors have beenidentified The greatest certainty is achieved for membrane

(MT1and MT

2) and nuclear (RZRROR120572 and RZRROR120573)

receptors Discussion regarding othermelatonin binding sitesis still far from complete Binding sites were found in differentparts of the cell in the membranes (GPR50) in the cytosol(MT3) and in the mitochondria [31]

Receptors and binding sites of melatonin are distributedthroughout the body Their greatest number is noted in vari-ous brain structures endocrine glands and some peripheralorgans [32 33] The distribution of receptors is organospe-cific Several types of binding sites may occur in the cells ofone organ MT

1receptors are predominant [1] Density and

affinity of receptors undergo significant changes during theday In the daytime when the concentration of melatonindecreases the number of its receptors is increasing [32 33]

31 Membrane Receptors MT1and MT

2 In the cells of vari-

ousmammalian species the two types ofmembrane receptorsare revealed MT

1and MT

2 formerly known as Mel

1a andMel1bMT

1is found in the hypothalamus the pituitary gland

cerebral cortex thalamus hippocampus cerebellum corneaand retina arteries heart lungs liver kidney adrenal glandskin and B and T lymphocytes [1 33 34] MT

2receptors are

localized in the hippocampus the cerebellum retina arteriesheart lungs liver small intestine and skin [1 32 35]

In humans the length of polypeptide chains is 350 and362 amino acids respectively MT

1and MT

2molecules

have high amino acid sequence homology (approximately60) [28] In accordance with the characteristics of theirspatial structure the MT

1MT2receptors belong to the

family of rhodopsin1205732-adrenergic receptors [36] They are

based on seven transmembrane 120572-helices connected by aseries of intra- and extracellular loops [34] The extracellularN-terminal fragment has the glycosylation sites and anintracellular C-terminal fragment includes phosphorylationsites [31 37] The palmitic acid residue can be attached to thecysteine residue of the fourth (intracellular) loop [38]

MT1and MT

2receptors have high affinity to melatonin

For molecules isolated from human cells 119870119889values are 807

and 383 pM respectively [39] Molecular mechanisms ofmelatonin binding to its receptors are far from sufficientlystudied It is assumed that the binding of 5-methoxyl groupof melatonin may involve residues of histidine (His195 in theMT1and His208 in the MT

2) and valine (Val-192) of the fifth

transmembrane helix The structure of pocket for bindingof melatoninrsquos N-acetyl group appears to differ for tworeceptors In the MT

1an important role belongs to the serine

residues (Ser110 and Ser114) in the third transmembranehelix whereas asparagine (Asn175) of the fourth helix hasgreater importance in the MT

2[28]

Recent works demonstrated polymorphisms of theMT1MT2receptors and related genes in human and animals

However these mutations did not have clear phenotypicexpression [28 40]

Membrane receptors are associated with G-protein how-ever depending on the tissue type intracellular signalingmechanisms may differ considerably The most commonis the suppression of cAMP synthesis by Gi-proteins bothsensitive and insensitive to pertussis toxin [34] This reduces

ISRN Biochemistry 3




1and MT
















2


1and MT

2form







2with the



1and MT

2[31 51] RZRROR120572 is






1and MT

2and structural


1and MT

2 As part





4 ISRN Biochemistry



3initially was



119894value






3was identified as





1and



1and MT

2 In


1and







1and MT

2 in recent years




2[66]


the MT1and MT






ISRN Biochemistry 5



1

NH

I


K2i = 250 pM

NHCOCH3


[65]

2

NH

OHO


K2i = 76nM


[66]

3

NH

HN

O NHCOCH3OCH3

K3i = 116pM

5MCA-NAT

Agonist MT3 [67]


4

N

H3CO

NHCOC3H7

K-185K1i

K2i


5

N

H3CO

NHCOC3H7

IIK7K1i

K2i

= 89Agonist MT2

[68]

6O


K2i = 45pM Agonist

MT1 and MT2

[65]

7

O

NHCOC2H5


K2i = 17pM

AgonistMT1 and MT2

[30]

6 ISRN Biochemistry

Table 1 Continued


8

NHCOCH3

H3CO K1i = 62pM

K2i = 268pM

AgomelatineAgonist

MT1 and MT2

[69]

9

NHCOC2H5

K1i

K2i

= 126

4P-PDOT

Antagonist MT2 [70]


10K2i

K1i

= 121

NHCOCH3

H3CCONH

Agonist MT1[70]

11 O O

NHCOCH3 H3CCONH

K2i

K1i

= 224

S26131

Antagonist MT1 [71]


12 N

S

NNHNH

S

O

H2C


Agonist RZRROR [72]



1198941198702

119894or11987021198941198701

119894



1and MT








ISRN Biochemistry 7









2is easier than MT

1[30]





1MT2and serotonin



5 Conclusion


1orMT







8 ISRN Biochemistry



References




































ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

ISRN Biochemistry 3




1and MT
















2


1and MT

2form







2with the



1and MT

2[31 51] RZRROR120572 is






1and MT

2and structural


1and MT

2 As part





4 ISRN Biochemistry



3initially was



119894value






3was identified as





1and



1and MT

2 In


1and







1and MT

2 in recent years




2[66]


the MT1and MT






ISRN Biochemistry 5



1

NH

I


K2i = 250 pM

NHCOCH3


[65]

2

NH

OHO


K2i = 76nM


[66]

3

NH

HN

O NHCOCH3OCH3

K3i = 116pM

5MCA-NAT

Agonist MT3 [67]


4

N

H3CO

NHCOC3H7

K-185K1i

K2i


5

N

H3CO

NHCOC3H7

IIK7K1i

K2i

= 89Agonist MT2

[68]

6O


K2i = 45pM Agonist

MT1 and MT2

[65]

7

O

NHCOC2H5


K2i = 17pM

AgonistMT1 and MT2

[30]

6 ISRN Biochemistry

Table 1 Continued


8

NHCOCH3

H3CO K1i = 62pM

K2i = 268pM

AgomelatineAgonist

MT1 and MT2

[69]

9

NHCOC2H5

K1i

K2i

= 126

4P-PDOT

Antagonist MT2 [70]


10K2i

K1i

= 121

NHCOCH3

H3CCONH

Agonist MT1[70]

11 O O

NHCOCH3 H3CCONH

K2i

K1i

= 224

S26131

Antagonist MT1 [71]


12 N

S

NNHNH

S

O

H2C


Agonist RZRROR [72]



1198941198702

119894or11987021198941198701

119894



1and MT








ISRN Biochemistry 7









2is easier than MT

1[30]





1MT2and serotonin



5 Conclusion


1orMT







8 ISRN Biochemistry



References




































ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

4 ISRN Biochemistry



3initially was



119894value






3was identified as





1and



1and MT

2 In


1and







1and MT

2 in recent years




2[66]


the MT1and MT






ISRN Biochemistry 5



1

NH

I


K2i = 250 pM

NHCOCH3


[65]

2

NH

OHO


K2i = 76nM


[66]

3

NH

HN

O NHCOCH3OCH3

K3i = 116pM

5MCA-NAT

Agonist MT3 [67]


4

N

H3CO

NHCOC3H7

K-185K1i

K2i


5

N

H3CO

NHCOC3H7

IIK7K1i

K2i

= 89Agonist MT2

[68]

6O


K2i = 45pM Agonist

MT1 and MT2

[65]

7

O

NHCOC2H5


K2i = 17pM

AgonistMT1 and MT2

[30]

6 ISRN Biochemistry

Table 1 Continued


8

NHCOCH3

H3CO K1i = 62pM

K2i = 268pM

AgomelatineAgonist

MT1 and MT2

[69]

9

NHCOC2H5

K1i

K2i

= 126

4P-PDOT

Antagonist MT2 [70]


10K2i

K1i

= 121

NHCOCH3

H3CCONH

Agonist MT1[70]

11 O O

NHCOCH3 H3CCONH

K2i

K1i

= 224

S26131

Antagonist MT1 [71]


12 N

S

NNHNH

S

O

H2C


Agonist RZRROR [72]



1198941198702

119894or11987021198941198701

119894



1and MT








ISRN Biochemistry 7









2is easier than MT

1[30]





1MT2and serotonin



5 Conclusion


1orMT







8 ISRN Biochemistry



References




































ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

ISRN Biochemistry 5



1

NH

I


K2i = 250 pM

NHCOCH3


[65]

2

NH

OHO


K2i = 76nM


[66]

3

NH

HN

O NHCOCH3OCH3

K3i = 116pM

5MCA-NAT

Agonist MT3 [67]


4

N

H3CO

NHCOC3H7

K-185K1i

K2i


5

N

H3CO

NHCOC3H7

IIK7K1i

K2i

= 89Agonist MT2

[68]

6O


K2i = 45pM Agonist

MT1 and MT2

[65]

7

O

NHCOC2H5


K2i = 17pM

AgonistMT1 and MT2

[30]

6 ISRN Biochemistry

Table 1 Continued


8

NHCOCH3

H3CO K1i = 62pM

K2i = 268pM

AgomelatineAgonist

MT1 and MT2

[69]

9

NHCOC2H5

K1i

K2i

= 126

4P-PDOT

Antagonist MT2 [70]


10K2i

K1i

= 121

NHCOCH3

H3CCONH

Agonist MT1[70]

11 O O

NHCOCH3 H3CCONH

K2i

K1i

= 224

S26131

Antagonist MT1 [71]


12 N

S

NNHNH

S

O

H2C


Agonist RZRROR [72]



1198941198702

119894or11987021198941198701

119894



1and MT








ISRN Biochemistry 7









2is easier than MT

1[30]





1MT2and serotonin



5 Conclusion


1orMT







8 ISRN Biochemistry



References




































ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

6 ISRN Biochemistry

Table 1 Continued


8

NHCOCH3

H3CO K1i = 62pM

K2i = 268pM

AgomelatineAgonist

MT1 and MT2

[69]

9

NHCOC2H5

K1i

K2i

= 126

4P-PDOT

Antagonist MT2 [70]


10K2i

K1i

= 121

NHCOCH3

H3CCONH

Agonist MT1[70]

11 O O

NHCOCH3 H3CCONH

K2i

K1i

= 224

S26131

Antagonist MT1 [71]


12 N

S

NNHNH

S

O

H2C


Agonist RZRROR [72]



1198941198702

119894or11987021198941198701

119894



1and MT








ISRN Biochemistry 7









2is easier than MT

1[30]





1MT2and serotonin



5 Conclusion


1orMT







8 ISRN Biochemistry



References




































ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

ISRN Biochemistry 7









2is easier than MT

1[30]





1MT2and serotonin



5 Conclusion


1orMT







8 ISRN Biochemistry



References




































ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

8 ISRN Biochemistry



References




































ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

ISRN Biochemistry 9








2melatonin



1MT2receptor





1andMT

2receptors































3melatonin










1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





1-agonist and MT




2





1and MT

2receptorsrdquo



1melatoniner-










vol 20 no 2 pp 289ndash300 2013









































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




















Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

reviewarticle synthetic melatoninergic ligands: achievements...

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