Melatonin
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🧬 Receptor activity
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Unchecked | — | Ki 0.05 nM | CHEMBL | TargetUnchecked Action— AffinityKi 0.05 nM SourceCHEMBL |
| Melatonin receptor type 1A | — | Ki 0.08 nM | CHEMBL | TargetMelatonin receptor type 1A Action— AffinityKi 0.08 nM SourceCHEMBL |
| Melatonin receptor | — | Ki 0.0823 nM | CHEMBL | TargetMelatonin receptor Action— AffinityKi 0.0823 nM SourceCHEMBL |
| Melatonin receptor type 1B | — | Ki 0.12 nM | CHEMBL | TargetMelatonin receptor type 1B Action— AffinityKi 0.12 nM SourceCHEMBL |
| Histamine H3 receptor | — | Ki 0.5 nM | CHEMBL | TargetHistamine H3 receptor Action— AffinityKi 0.5 nM SourceCHEMBL |
| Ribosyldihydronicotinamide dehydrogenase [quinone] | — | Ki 27.6 nM | CHEMBL | TargetRibosyldihydronicotinamide dehydrogenase [quinone] Action— AffinityKi 27.6 nM SourceCHEMBL |
| Cytochrome P450 1A2 | — | Ki 12000 nM | CHEMBL | TargetCytochrome P450 1A2 Action— AffinityKi 12000 nM SourceCHEMBL |
| Cytochrome P450 1B1 | — | Ki 14000 nM | CHEMBL | TargetCytochrome P450 1B1 Action— AffinityKi 14000 nM SourceCHEMBL |
| Cytochrome P450 1A1 | — | Ki 59000 nM | CHEMBL | TargetCytochrome P450 1A1 Action— AffinityKi 59000 nM SourceCHEMBL |
Mechanism of action
Melatonin is a derivative of tryptophan. It binds to melatonin receptor type 1A, which then acts on adenylate cylcase and the inhibition of a cAMP signal transduction pathway. Melatonin not only inhibits adenylate cyclase, but it also activates phosphilpase C. This potentiates the release of arachidonate. By binding to melatonin receptors 1 and 2, the downstream signallling cascades have various effects in the body. The melatonin receptors are G protein-coupled receptors and are expressed in various tissues of the body. There are two subtypes of the receptor in humans, melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin and melatonin receptor agonists, on market or in clinical trials, all bind to and activate both receptor types.The binding of the agonists to the receptors has been investigated for over two decades or since 1986. It is somewhat known, but still not fully understood. When melatonin receptor agonists bind to and activate their receptors it causes numerous physiological processes. MT1 receptors are expressed in many regions of the central nervous system (CNS): suprachiasmatic nucleus of the hypothalamus (SNC), hippocampus, substantia nigra, cerebellum, central dopaminergic pathways, ventral tegmental area and nucleus accumbens. MT1 is also expressed in the retina, ovary, testis, mammary gland, coronary circulation and aorta, gallbladder, liver, kidney, skin and the immune system. MT2 receptors are expressed mainly in the CNS, also in the lung, cardiac, coronary and aortic tissue, myometrium and granulosa cells, immune cells, duodenum and adipocytes. The binding of melatonin to melatonin receptors activates a few signaling pathways. MT1 receptor activation inhibits the adenylyl cyclase and its inhibition causes a rippling effect of non activation; starting with decreasing formation of cyclic adenosine monophosphate (cAMP), and then progressing to less protein kinase A (PKA) activity, which in turn hinders the phosphorilation of cAMP responsive element-binding protein (CREB binding protein) into P-CREB. MT1 receptors also activate phospholipase C (PLC), affect ion channels and regulate ion flux inside the cell. The binding of melatonin to MT2 receptors inhibits adenylyl cyclase which decreases the formation of cAMP.[4] As well it hinders guanylyl cyclase and therefore the forming of cyclic guanosine monophosphate (cGMP). Binding to MT2 receptors probably affects PLC which increases protein kinase C (PKC) activity. Activation of the receptor can lead to ion flux inside the cell.
Melatonin is implicated in numerous physiological processes, including circadian rhythms, stress, and reproduction, many of which are mediated by the hypothalamus and pituitary. The physiological actions of melatonin are mainly mediated by melatonin receptors. /The authors/ describe the distribution of the melatonin receptor MT1 in the human hypothalamus and pituitary by immunocytochemistry. MT1 immunoreactivity showed a widespread pattern in the hypothalamus. In addition to the area of the suprachiasmatic nucleus (SCN), a number of novel sites, including the paraventricular nucleus (PVN), periventricular nucleus, supraoptic nucleus (SON), sexually dimorphic nucleus, the diagonal band of Broca, the nucleus basalis of Meynert, infundibular nucleus, ventromedial and dorsomedial nucleus, tuberomamillary nucleus, mamillary body, and paraventricular thalamic nucleus were observed to have neuronal MT1 receptor expression. No staining was observed in the nucleus tuberalis lateralis and bed nucleus of the stria terminalis. The MT1 receptor was colocalized with some vasopressin (AVP) neurons in the SCN, colocalized with some parvocellular and magnocellular AVP and oxytocine (OXT) neurons in the PVN and SON, and colocalized with some parvocellular corticotropin-releasing hormone (CRH) neurons in the PVN. In the pituitary, strong MT1 expression was observed in the pars tuberalis, while a weak staining was found in the posterior and anterior pituitary. These findings provide a neurobiological basis for the participation of melatonin in the regulation of various hypothalamic and pituitary functions. The colocalization of MT1 and CRH suggests that melatonin might directly modulate the hypothalamus-pituitary-adrenal axis in the PVN, which may have implications for stress conditions such as depression.
A major mechanism through which melatonin reduces the development of breast cancer is based on its anti-estrogenic actions by interfering at different levels with the estrogen-signalling pathways. Melatonin inhibits both aromatase activity and expression in vitro (MCF-7 cells) as well as in vivo, thus behaving as a selective estrogen enzyme modulator. The objective of this study was to study the effect of MT1 melatonin receptor overexpression in MCF-7 breast cancer cells on the aromatase-suppressive effects of melatonin. Transfection of the MT1 melatonin receptor in MCF-7 cells significantly decreased aromatase activity of the cells and MT1-transfected cells showed a level of aromatase activity that was 50% of vector-transfected MCF-7 cells. The proliferation of estrogen-sensitive MCF-7 cells in an estradiol-free media but in the presence of testosterone (an indirect measure of aromatase activity) was strongly inhibited by melatonin in those cells overexpressing the MT1 receptor. This inhibitory effect of melatonin on cell growth was higher on MT1 transfected cells than in vector transfected ones. In MT1-transfected cells, aromatase activity (measured by the tritiated water release assay) was inhibited by melatonin (20% at 1 nM; 40% at 10 microM concentrations). The same concentrations of melatonin did not significantly influence the aromatase activity of vector-transfected cells. MT1 melatonin receptor transfection also induced a significant 55% inhibition of aromatase steady-state mRNA expression in comparison to vector-transfected MCF-7 cells (p<0.001). In addition, in MT1-transfected cells melatonin treatment inhibited aromatase mRNA expression and 1 nM melatonin induced a higher and significant down-regulation of aromatase mRNA expression (p<0.05) than in vector-transfected cells. The findings presented herein point to the importance of MT1 melatonin receptor in mediating the oncostatic action of melatonin in MCF-7 human breast cancer cells and confirm MT1 melatonin receptor as a major mediator in the melatonin signalling pathway in breast cancer.
Almost all the melatonin formed in mammals is synthesized within the pineal gland... The tryptophan is first 5-hydroxylated (by the enzyme tryptophan hydroxylase) and then decarboxylated (by the enzyme aromatic L-amino acid decarboxylase) to form 5-hydroxytryptamine or serotonin. During daylight hours, the serotonin in pinealocytes tends to be stored, and is unavailable to enzymes (monoamine oxidase and the melatonin-forming enzymes) that would otherwise act on it. With the onset of darkness, postganglionic sympathetic outflow to the pineal increases, and the consequent release of norepinephrine onto pinealocytes causes stored serotonin to become accessible for intracellular metabolism. At the same time, the norepinephrine activates the enzymes (especially serotonin-N-acetyltransferase (SNAT), but also hydroxyindole-O-methyltransferase (HIOMT)) that convert serotonin to melatonin. Consequently, pineal melatonin levels rises manifold. ... The melatonin then diffuses out of the pineal gland into the blood stream and cerebrospinal fluid, rapidly raising human plasma melatonin levels from about 2-10 to 100-200 pg/mL.
Pharmacodynamics
Melatonin is a hormone normally produced in the pineal gland and released into the blood. The essential amino acid L-tryptophan is a precursor in the synthesis of melatonin. It helps regulate sleep-wake cycles or the circadian rhythm. Production of melatonin is stimulated by darkness and inhibited by light. High levels of melatonin induce sleep and so consumption of the drug can be used to combat insomnia and jet lag. MT1 and MT2 receptors may be a target for the treatment of circadian and non circadian sleep disorders because of their differences in pharmacology and function within the SCN. SCN is responsible for maintaining the 24 hour cycle which regulates many different body functions ranging from sleep to immune functions
Pharmacokinetics
Half-life
35 to 50 minutes
...The terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 hr-1). ...
Absorption
The absorption and bioavailability of melatonin varies widely.
To determine whether melatonin pharmacokinetics change during puberty, ... melatonin /was infused/ iv in 9 prepubertal, 8 pubertal, and 16 adult subjects and melatonin in serum and saliva and 6-hydroxymelatonin sulfate in urine /were measured/. A pilot study of 3 adult males showed dose linearity, absence of saturation kinetics, and unaltered metabolism and urinary excretion for doses of 0.1, 0.5, and 5.0 ug/kg. All other subjects received 0.5 ug/kg melatonin. The results of pharmacokinetic parameters calculated from serum melatonin showed no significant gender differences in adults. However, developmental differences were significant between prepubertal children and adults for terminal elimination rate constant (1.08 +/- 0.25 vs. 0.89 +/- 0.11 per hr), elimination half-life (0.67 +/- 0.12 vs. 0.79 +/- 0.10 hr), and area under the concentration-time curve (250.9 +/- 91.8 vs. 376.9 +/- 154.3 (pg/mL)hr, respectively). At all time points melatonin levels were higher in serum than in saliva, and the ratio between serum and salivary melatonin varied up to 55-fold within and between individuals. Results based on salivary melatonin showed significant differences between prepubertal children and adults for the terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 per hr). The described group differences in pharmacokinetic parameters suggest that prepubertal children metabolize melatonin faster than adults. The inconsistent ratio between serum and salivary melatonin calls for caution in the use of salivary melatonin for pharmacokinetic studies or to infer pineal function. The present findings, suggestive of faster melatonin metabolism in prepubertal children, combined with the known decline of serum melatonin with age and higher excretion rate of the metabolite in prepubertal children lead us to conclude that the prepubertal pineal gland has a higher melatonin secretion rate than the adult gland.
The pharmacokinetics of melatonin during the day-time has been studied in 4 healthy subjects after a bolus i.v. injection of 5 or 10 ug/person and after a 5 hr infusion of 20 ug per person in 6 healthy subjects. In addition, a pinealomectomized patient whose nocturnal plasma melatonin had been abolished was investigated after the i.v. infusion--once during the night and once during the day. The clearance of melatonin from blood showed a biexponential decay. The pharmacokinetic parameters in the two studies were similar, except for the disappearance rate constant beta and the apparent volume of distribution at steady-state (Vss). Supplementary peaks or troughs were superimposed on the plateau and the falling part of the profile. They were not due to stimulation of endogenous secretion, because they were also seen in the pinealomectomized patient. During the melatonin infusion, the plasma hormone level reached a steady-state after 60 and 120 min, and when it was equal to the nocturnal level.
... In a randomized and double-blind controlled study 10 healthy male subjects undertook an 80 min intensive hypertrophic heavy resistance exercise session (RES) for major muscles of the lower and upper extremities. The subjects were studied on two occasions receiving either melatonin (6 mg) or placebo (6 mg) in random order 60 min before each RES. Blood samples were taken from an antecubital vein both in fasting conditions in the morning and before RES (pre 60 min, pre 0 min), during RES (middle) and after RES (post 0 min, post 15 min, post 30 min, post 60 min). ... The serum melatonin concentration increased significantly (P<0.05-0.001) in the melatonin group following oral ingestion of melatonin and was elevated at every time point after that. The concentration reached a peak value of 1171.3+/-235.2 pg/mL in 60 min at pre 0. Serum melatonin increased slightly but significantly (P<0.05) also in the placebo group just before RES, in the middle of RES and after RES (post 0, post 15). There were large differences (P<0.01-0.001) in the serum melatonin concentration between the groups at all time points. ...
...Pharmacokinetics of melatonin was studied in rats, dogs, and monkeys following intravenous and oral administrations, and the absolute oral bioavailability of melatonin was calculated from the area under the plasma concentration-time curve. The apparent elimination half-life of melatonin following an intravenous dose of 3 mg/kg (5 mg/kg in rats) was 19.8, 18.6, and 34.2 minutes, respectively, in rats, dogs, and monkeys. The dose normalized oral bioavailability of melatonin following a 10 mg/kg oral dose was 53.5% in rats, while it was in excess of 100% in dogs and monkeys. Further, bioavailability of melatonin following a 10 mg/kg intraperitoneal administration in rats was 74.0%, suggesting the lack of substantial first-pass hepatic extraction of melatonin in rats. However, the oral bioavailability of melatonin in dogs decreased to 16.9% following a 1 mg/kg oral dose, indicating dose-dependent bioavailability in dogs.
For more Absorption, Distribution and Excretion (Complete) data for MELATONIN (11 total), please visit the HSDB record page.
Metabolism
Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine).
Most of the melatonin in the circulation is inactivated in the liver where it is first oxidized to 6-hydroxy melatonin by a P450-dependent microsomal oxidase and then largely conjugated to sulfate or glucuronide before being excreted into urine or feces.
In humans, the pineal hormone melatonin (MEL) is principally metabolized to 6-hydroxymelatonin (6-HMEL), which is further conjugated with sulfate and excreted in urine. MEL O-demethylation represents a minor reaction. The exact role of individual human cytochromes P450 (P450s) in these pathways has not been established. /The authors/ used a panel of 11 recombinant human P450 isozymes to investigate for the first time the 6-hydroxylation and O-demethylation of MEL. CYP1A1, CYP1A2, and CYP1B1 all 6-hydroxylated MEL, with CYP2C19 playing a minor role. These reactions were NADPH-dependent. CYP2C19 and, to some extent CYP1A2, O-demethylated MEL. The K(m) (uM) and V(max) (k(cat), pmol/ min/ pmol P450) for 6-hydroxylation were estimated as 19.2 +/- 2.01 and 6.46 +/- 0.22 (CYP1A1), 25.9 +/- 2.47 and 10.6 +/- 0.32 (CYP1A2), and 30.9 +/- 3.76 and 5.31 +/- 0.21 (CYP1B1). These findings confirm the suggestion of others that CYP1A2 is probably the foremost hepatic P450 in the 6-hydroxylation of MEL and a single report that CYP1A1 is also able to mediate this reaction. However, this is the first time that CYP1B1 has been shown to 6-hydroxylate MEL. The IC50 for the CYP1B1-selective inhibitor (E)-2,4,3',5'-tetramethoxystilbene was estimated to be 30 nM for MEL 6-hydroxylation by recombinant human CYP1B1. Comparison of brain homogenates from wild-type and cyp1b1-null mice revealed that MEL 6-hydroxylation was clearly mediated to a significant degree by CYP1B1. CYP1B1 is not expressed in the liver but has a ubiquitous extrahepatic distribution, and is found at high levels in tissues that also accumulate either MEL or 6-HMEL, such as intestine and cerebral cortex, where it may assist in regulating levels of MEL and 6-HMEL.
Melatonin is synthesized at night in the human pineal gland and released into the blood and cerebrospinal fluid. It acts on the brains of humans to promote sleep, and also influences the phasing of sleep and various other circadian rhythms. During the day, plasma melatonin levels are low; at night, they rise 10 to 100-fold or more in young adults, but by considerably less in older people- who often may have frequent nocturnal awakenings as a consequence. Very small oral doses of melatonin raise daytime plasma melatonin to night-time levels, thus making it easier for people to fall asleep in the afternoon or evening. Such doses can also help older people remain asleep during the night. Melatonin has also occasionally been claimed to confer other medical benefits e.g. preventing such age-related diseases as atherosclerosis, cancer, and alzheimer's disease. The evidence in such claims is sparse.
Melatonin has known human metabolites that include 6-[3-(2-Acetamidoethyl)-5-methoxyindol-1-yl]-3,4,5-trihydroxyoxane-2-carboxylic acid, 6-Hydroxymelatonin, and N-Acetyl-5-hydroxytryptamine.
Hepatically metabolized to at least 14 identified metabolites (identified in mouse urine): 6-hydroxymelatonin glucuronide, 6-hydroxymelatonin sulfate, N-acetylserotonin glucuronide, N-acetylserotonin sulfate, 6-hydroxymelatonin, 2-oxomelatonin, 3-hydroxymelatonin, melatonin glucuronide, cyclic melatonin, cyclic N-acetylserotonin glucuronide, cyclic 6-hydroxymelatonin, 5-hydroxyindole-3-acetaldehyde, di-hydroxymelatonin and its glucuronide conjugate. 6-Hydroxymelatonin glucuronide is the major metabolite found in mouse urine (65-88% of total melatonin metabolites in urine).
Half Life: 35 to 50 minutes
Protein binding
n/a
External links
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