A Review of Melatonin , Its Receptors and Drugs Bir Melatonin Derlemesi , Reseptörleri ve İlaçları

After a Turkish scientist took Nobel Prize due to his contributions to understand clock genes, melatonin, closely related to these genes, may begin to shine. Melatonin, a hormone secreted from the pineal gland at night, plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation. Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic, locomotor activityregulating, neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reducing, retinal, vascular, anti-tumor and antioxidant effects. It is related with memory, ovarian physiology, and osteoblast differentiation. Pathologies associated with an increase or decrease in melatonin levels are summarized in the review. Melatonin affects by four mechanisms: 1) Binding to melatonin receptors in plasma membrane, 2) Binding to intracellular proteins such as calmoduline, 3) Binding to Orphan nuclear receptors, and 4) Antioxidant effect. Receptors associated with melatonin are as follows: 1) Melatonin receptor type 1a: MT1 (on cell membrane), 2) Melatonin receptor type 1b: MT2 (on cell membrane), 3) Melatonin receptor type 1c (found in fish, amphibians and birds), 4) Quinone reductase 2 enzyme (MT3 receptor, a detoxification enzyme), 5) RZR/RORα: Retinoid-related Orphan nuclear hormone receptor (with this receptor, melatonin binds to the transcription factors in nucleus), and 6) GPR50: X-linked Melatonin-related Orphan receptor (it is effective in binding of melatonin to MT1). Melatonin agonists such as ramelteon, agomelatine, circadin, TIK-301 and tasimelteon are introduced and side effects will be discussed. In conclusion, melatonin and related drugs is a new and promising era for medicine. Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future.


Melatonin and Associated Pathologies
Melatonin is a hormone secreted from the pineal gland at night.Its peak levels in the dark are associated with age as well as various illnesses (Figure 1).Melatonin plays roles in regulating sleep-wake cycle, pubertal development and seasonal adaptation [1].Melatonin is related with memory, and its associations with control of body posture and bal-ance have been shown [1].Melatonin regulates memory formation by directly affecting hippocampal neurons [2].Melatonin has antinociceptive, antidepressant, anxiolytic, antineophobic (being afraid of new things) and locomotor activity-regulating effects [3].There are neuroprotective, anti-inflammatory, pain-modulating, blood pressure-reduc-ing, retinal, vascular, seasonal reproductive, ovarian physiology, osteoblast differentiation, anti-tumor and antioxidant effects of melatonin [2,4].
Dopaminergic system is important for behavior and rewarding and also in cases of drug addiction such as cocaine [3].Melatonin inhibits dopamine release [3].The increase in melatonin receptor-related cAMP in the mesolimbic dopaminergic system shows that the effect of melatonin may be present in regulation of addictive behavior [1].It corrects the behavior disorders related to dopamine addiction and alleviates the findings of cocaine abstinence [3].Other effects of melatonin are inhibition of dopamine release in hypothalamus and retina [1].The anti-excitatory effects of melatonin are probably secondary to its antioxidant effect [5].When it is administered in pharmacological doses in children, it leads to reduction in severity and frequency of epileptiform activity [6].It shows an effect contrary to glutamate, which is an excitatory neurotransmitter, i.e. it is an inhibitor [3].
High melatonin level is associated with exercise-related menstrual disorders, oligospermia and delayed puberty [7].Melatonin regulates the secretion of gonadotrophin-releasing hormone (GnRH) from the hypothalamic neurons [8].GnRH controls the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).Melatonin stimulates the secretion of progesterone from granulosa cells [8].Melatonin also suppresses the expression of estrogen receptor and estrogen activation [9].
The disorders in which variations in production of endogenous melatonin production were shown are as follows: Sleep disorders, Alzheimer's disease, Parkinson's disease, glaucoma, depression, breast cancer, prostate cancer, hepatoma, melanoma, congestive heart failure, cardiac syndrome X and sepsis [1,21].Melatonin production is reduced with aging, various cancers, Alzheimer's disease, senile dementia, pineal calcification [22], cardiovascular disorders and hypothalamic hamartoma or craniopharyngioma which lead to precocious puberty in youngsters [1,23].Other disorders in which melatonin was shown to be reduced are stress, pain, endocrine and metabolic disorders, particularly DM type 2 and acute intermittent porphyria [24].
Intravenous administration of melatonin increases peripheral blood circulation [25].Melatonin directly leads to vasoconstriction in cerebral arteries [8].Daytime melatonin administration lowers the body temperature due to vasodilation in distal parts of the body [1,26,27].The effects of melatonin on blood vessels seem to be related to its noradrenergic effects and/or its effects on NO [21].Vasodilator and peripheral resistance-reducing effect may be related to NO potentialisation, anti-noradrenergic mechanism or inhibition of vasopressin release [21].Activation of MT1 receptors leads to vasoconstriction and activation of MT2 receptors leads to vasodilation [1].

The Mechanism of Effect of Melatonin
Melatonin shows its affects by four mechanisms in mammals: 1. Binding to melatonin receptors in plasma membrane 2. Binding to intracellular proteins such as calmoduline 3. Binding to Orphan nuclear receptors 4. Antioxidant effect [21] (Figure 2) Melatonin interacts with intracellular proteins named calmoduline, calreticulin and tubulin [1].Calmoduline is an intracellular secondary messenger.Melatonin directly antagonizes binding of calcium to calmoduline [1,21] (Figure 2).The anti-proliferative effect in cancer may be related to this.Retinoid-related Orphan nuclear hormone receptor family (RZR/ROR) is responsible for the immunomodulatory effects of melatonin.IL-2 and IL-6 are produced in mononuclear cells by this mechanism [21] (Figure 2).

Melatonin receptors
The locations that melatonin receptors are found in the body are as follows: brain, retina, cardiovascular system, cardiac ventricular wall, aorta, coronary and cerebral arteries, liver and gallbladder, duodenal enterocytes, colon, cecum and appendix vermiformis, skin, parotid gland, exocrine pancreas, kidney, cells of immune system, platelets, brown and white adipocytes, epithelial cells of prostate and breast, ovary/granulosa cells, myometrium, placenta and fetal kidney [3,24].In gastrointestinal system, melatonin receptors are found most commonly in jejunal and colonic mucosa [1].
There are three different membrane receptors and one nuclear receptor: 1. Melatonin receptor type 1a: Mel 1a, ML1a, ML1, MT1, MTNR1A It is encoded in human chromosome #4 and consists of 351 amino acids [4].MT1 receptor constitutes adenylate cyclase inhibition by binding to various G-proteins [2].MT1 receptors are commonly found in human skin [1].During aging process and Alzheimer's disease, the expression of MT1 receptor in suprachiasmatic nucleus (SCN) and cortex decreases [1]  and the production of cyclic AMP (cAMP) is reduced [28,29].
In the skin, MT2 receptors are located within normal and malign melanocytes and eccrine sweat glands [1].MT2 receptors inhibit GABA-A receptor-related functions in the hippocampus in rats [8].In Alzheimer's disease, MT2 receptor expression is reduced.MT2 receptors are involved in antidepressant activity [24].MT2 receptors contribute to the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer's disease and pain [2].MT2 receptors may be the new target for development of hypnotic agents [2] [31].Its gene is located on the X chromosome (Xq28) and consists of 618 amino acids [4].It is present in all mammalians including humans.It does not have the characteristics of binding to melatonin [21]; however, it is effective in binding of melatonin to MT1 [32].GPR50 is not present in birds and fish [4,33].It is located in the brain and periphery.Its natural ligand has not been defined yet.It was reported that a deletion mutant in GPR50 might have been associated with bipolar disorder and major depression [34].GPR50 has no affinity to melatonin; however, when it dimerizes with MT1, it inhibits the melatonin signal [29,35].GPR50 has other functions apart from melatonin [4].GPR50 interacts [4] with neurite outgrow inhibitor (NOGO-A) [4,36] and TIP60 (glucocorticoid receptor signal coactivator and histone acetyltransferase) [4,37].After MT1 and MT2 receptors adhere to the cell surface, they create their effects through G-protein.Activation of MT1 receptor leads to inhibition of cAMP formation which was stimulated by forkolin, together with inhibition of Protein kinase A (PKA) [21].Similarly, activation of MT2 receptor leads to inhibition of cAMP formation, which was stimulated by forkolin [21].Additionally, it inhibits formation of cGMP [21].While membrane receptors are basically located in the central nervous system, RZR/RORα is located at both periphery and the brain [9].Membrane receptors and their specific agonists are associated with circadian rhythm, whereas RZR/ RORα seems to be responsible for immunomodulation at the periphery, cellular growth and differentiation of bone [9].Activation of Protein kinase C-α is a critical step in the formation of melatonin effect [1].
Development of pharmacological agents, which are effective on MT receptors, may be associated with antihypertensive, anti-cancer or immunostimulant effects or they may facilitate falling asleep [21].In addition to its anti-inflammatory effect, its immunostimulant effect is an undesired situation in autoimmune disorders and melatonergic drugs may be contraindicated in such patients [24].For example, melatonin aggravates the symptoms of rheumatoid arthritis by stimulating proinflammatory cytokines [38].

Melatonin Agonist Pharmaceuticals
For people having difficulties in falling asleep, short-acting drugs are sufficient.Melatonin reduces the sleep latency, even small doses such as 0.1-0.3mg/day are sufficient for this purpose [39].All synthetic melatonergic drugs can provide this effect.
1) Ramelteon (Rozerem©, Takeda, Japan; TAK-375): It is a non-selective (MT1/MT2) melatonin receptor agonist.In US, it received approval from FDA in 2005 for treatment of insomnia in individuals having difficulty in falling asleep [40].Ramelteon is rapidly Eurasian J Med 2016; 48: 135-41 absorbed from gastrointestinal system with a rate of 84% and its half-life in blood circulation is 1-2 hours [41].Among melatonergic agonist drugs, Ramelteon is the one having relatively higher affinity to both receptor subtypes [24].In elderly individuals having primary chronic insomnia, the effect of Ramelteon in maintaining sleep has been found to be highly variable [42].Ramelteon is metabolized basically by CYP1A2, CYP2C9 and CYP3A4 [43].2) Agomelatine (Valdoxan©, Servier, France; S20098): In November 2008, it received approval from EMA (European Medicines Agency) in Europe for treatment of major depression in adults [2,24,44].It is a non-selective (MT1/MT2) melatonin receptor agonist + serotonergic 5-HT 2c antagonist.It is the first reported melatonergic drug having anxiolytic and antidepressant effects [1].In major depression, it is used with a daily dose of 25 mg.In seasonal affective disorder, it can be effective in very small doses (0.225-0.3 mg/day), without affecting sleep [45].The half-life of agomelatine is 1-2 hours [24].Inhibition of 5HT2c is held responsible for its direct antidepressant effect [46].The advantage of agomelatin is not its better antidepressant effect, but its improving effect on sleep together with its antidepressant effects.Indeed, conventional antidepressants often trigger sleep disorders [24].Agomelatine is metabolized basically by CYP1A1, CYP1A2 and CYP2C9 [43].3) Melatonin controlled release tablets (prolonged release melatonin) (Circadin©, Neurim, Israel and UK): It received approval from EMA (European Medicines Agency) for insomnia treatment in patients over 55 years of age in Europe [24].Its dose is 2 mg/day.In a study conducted on Amyotrophic lateral sclerosis patients, even doses of 300 mg/day for up to 2 years was found to be safe [47].
The affinity of natural melatonin hormone is higher to MT1 than MT2.This situation is valid for ramelteon and agomelatine, also [24].The circulatory half-life of melatonin is very short, being 20-30 minutes in average with a maximum of 45 minutes [48].As a solution for this problem, controlled release tablets of the hormone or synthetic products with longer half-lives were developed.4) TIK-301: It is a melatonergic agonist and serotonergic antagonist drug.It is a more powerful antagonist of serotonergic 5-HT 2c and 5-HT 2b receptors when compared to agomelatine [49].Theoretically, it has an antidepressant effect.Its half-life is one hour [50].
It received approval from FDA for using in sleep disorders of visually impaired individuals [24].5) Tasimelteon (Hetlioz, Vanda Pharmaceuticals, USA): It is approved by FDA in January, 2014 for the treatment of non-24-hour sleep-wake disorder.Later in July 2015, it was approved in Europe for the treatment of non-24-hour sleep-wake rhythm disorder in totally blind adults.Its half-life is approximately 2 hours.Its sleep-initiating and antidepressant effects are on trial [24].It is basically metabolized by CYP1A1, CYP1A2, CYP2D6 and CYP2C9 [43].
Liver failure, renal failure, alcohol addiction and high lipid levels are contraindications for melatonin agonists [51].
The adverse effects of melatonin agonists are as follows: nausea, headache and elevations in some liver parameters, rebound insomnia, withdrawal symptoms when used for 6 to 12 months or addiction [24].There is a risk for hepatotoxicity [52].In experimental animal studies, it is carcinogenic in very high doses [52].
In a recent systematic review, the most common side effects related to melatonin agonists have been reported as headache, somnolence, palpitations and abdominal pain [53].Rarely reported side effects are nasopharyngitis, arthralgia, tachycardia, dizziness, nausea, vomiting, nightmares, difficulties in swallowing and breathing, hypnotic activity, feeling of heaviness in the head, heartburn, belching, arm and leg swelling, sweating, hot flushes, exanthema, sleep problems, depression and sleep-walking [53].A brief summary of altered melatonin metabolism on different systems and pathologies are demonstrated in Table 1.

Conclusion
Melatonin and related drugs are a new and promising era for medicine.Melatonin is highly associated with circadian rhythm and circadian clock genes.The first Turkish scientist and biochemist Aziz Sancar was honored by Nobel Prize due to his contributions to understand the mechanism in this field.Hypothalamic suprachiasmatic nucleus expresses various clock genes in a rhythmic fashion.For example expressions in diurnal variations in per1, a clock gene, depends on pineal gland and melatonin secretion [55].Melatonin receptors and melatonin drugs will take attention with greater interest day by day in the future.

Figure 1 .
Figure 1.Peak melatonin levels at night tend to decrease with advanced age in human.

Table 1 . Altered melatonin metabolism on different systems and pathologies
Emet et al.Melatonin, Its Receptors and Drugs Eurasian J Med 2016; 48: 135-41