N-Acetylserotonin

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N-Acetylserotonin
N-Acetylserotonin.png
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Names
Preferred IUPAC name
N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]acetamide
Other names
N-Acetyl-5-hydroxytryptamine
N-Acetyl-5-HT
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.013.560 OOjs UI icon edit-ltr-progressive.svg
MeSH N-Acetylserotonin N-Acetylserotonin
PubChem CID
UNII
  • InChI=1S/C12H14N2O2/c1-8(15)13-5-4-9-7-14-12-3-2-10(16)6-11(9)12/h2-3,6-7,14,16H,4-5H2,1H3,(H,13,15) Yes check.svgY
    Key: MVAWJSIDNICKHF-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C12H14N2O2/c1-8(15)13-5-4-9-7-14-12-3-2-10(16)6-11(9)12/h2-3,6-7,14,16H,4-5H2,1H3,(H,13,15)
    Key: MVAWJSIDNICKHF-UHFFFAOYAX
  • CC(=O)NCCC1=CNC2=C1C=C(C=C2)O
Properties
C12H14N2O2
Molar mass 218.256 g·mol−1
Density 1.268 g/mL
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. [1] [2] It also has biological activity in its own right, including acting as a melatonin receptor agonist, an agonist of the TrkB, and having antioxidant effects.

Contents

Biological function

Like melatonin, NAS is an agonist at the melatonin receptors MT1, MT2, and MT3, and may be considered to be a neurotransmitter. [3] [4] [5] [6] In addition, NAS is distributed in some areas of the brain where serotonin and melatonin are not, suggesting that it may have unique central duties of its own instead of merely functioning as a precursor in the synthesis of melatonin. [3] NAS is known to have anti-depressant, neurotrophic and cognition-enhancing effects [7] [8] and has been proposed to be a target for the treatment of aging-associated cognitive decline and depression [8]

TrkB receptor

NAS has been shown to act as a potent TrkB receptor agonist, while serotonin and melatonin do not. [3] Subchronic and chronic administration of NAS to adult mice induces proliferation of neural progenitor cells (NPC)s, blockage of TrkB abolished this effect suggesting that it is TrkB-dependent. [9] NAS was also found to significantly enhance NPC proliferation in sleep-deprived mice. [9] It is thought that the anti-depressant and neurotrophic effects of NAS are in part due to its role as a TrkB agonist. [7]

Antioxidant properties

NAS acts as a potent antioxidant, NAS effectiveness as an anti-oxidant has been found to be different depending on the experimental model used, it has been described as being between 5 and 20 times more effect than melatonin at protecting against oxidant damage. [10] NAS has been shown to protect against lipid peroxidation in microsomes and mitochondria. [11] NAS has also been reported to lower resting levels of ROS in peripheral blood lymphocytes and to exhibit anti-oxidant effects against t-butylated hydroperoxide- and diamide-induced ROS. [12] NAS has also been observed to inhibit nitric oxide synthase. [13]

Anti-inflammatory effects

NAS has been reported to have anti-inflammatory effects. NAS has been shown to inhibit LPS-stimulated production of the proinflammatory cytokine TNF-alpha in differentiated THP-1-derived human monocytes. [14]

Miscellaneous

NAS may play a role in the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). [3] The SSRI fluoxetine and the MAO-A inhibitor clorgyline upregulate AANAT indirectly through serotonergic mechanisms and thereby increase NAS levels after chronic administration, and this correlates with the onset of their antidepressant effects. [3] [15] Furthermore, light exposure inhibits the synthesis of NAS and reduces the antidepressant effects of MAOIs. [3] In addition, AANAT knockout mice display significantly greater immobility times versus control mice in animal models of depression. [3] These data support a potential role for NAS in mood regulation and in antidepressant-induced therapeutic benefits.

Through a currently unidentified mechanism, NAS may be the cause of the orthostatic hypotension seen with clinical treatment of MAOIs. [15] [16] It reduces blood pressure in rodents, and pinealectomy (the pineal gland being a major site of NAS and melatonin synthesis) abolishes the hypotensive effects of clorgyline. [15] [16]

Biochemistry

NAS is produced from serotonin by the enzyme aralkylamine N-acetyltransferase (AANAT) and is converted to melatonin by acetylserotonin O-methyltransferase (ASMT).

NAS is able to penetrate the blood–brain barrier, unlike serotonin. [17]

See also

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<span class="mw-page-title-main">Monoamine oxidase inhibitor</span> Type of medication

Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, especially for treatment-resistant depression and atypical depression. They are also used to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.

<span class="mw-page-title-main">Melatonin</span> Hormone released by the pineal gland

Melatonin is a natural compound, specifically an indoleamine, produced by and found in different organisms including bacteria and eukaryotes. It was discovered by Aaron B. Lerner and colleagues in 1958 as a substance of the pineal gland from cow that could induce skin lightening in common frogs. It was subsequently discovered as a hormone released in the brain at night which controls the sleep–wake cycle in vertebrates.

<span class="mw-page-title-main">5-HT receptor</span> Class of transmembrane proteins

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.

<span class="mw-page-title-main">Ramelteon</span> Hypnotic medication

Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia. It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset. It reduces the time taken to fall asleep, but the degree of clinical benefit is small. The medication is approved for long-term use. Ramelteon is taken by mouth.

Melatonin receptors are G protein-coupled receptors (GPCR) which bind melatonin. Three types of melatonin receptors have been cloned. The MT1 (or Mel1A or MTNR1A) and MT2 (or Mel1B or MTNR1B) receptor subtypes are present in humans and other mammals, while an additional melatonin receptor subtype MT3 (or Mel1C or MTNR1C) has been identified in amphibia and birds. The receptors are crucial in the signal cascade of melatonin. In the field of chronobiology, melatonin has been found to be a key player in the synchrony of biological clocks. Melatonin secretion by the pineal gland has circadian rhythmicity regulated by the suprachiasmatic nucleus (SCN) found in the brain. The SCN functions as the timing regulator for melatonin; melatonin then follows a feedback loop to decrease SCN neuronal firing. The receptors MT1 and MT2 control this process. Melatonin receptors are found throughout the body in places such as the brain, the retina of the eye, the cardiovascular system, the liver and gallbladder, the colon, the skin, the kidneys, and many others. In 2019, X-ray crystal and cryo-EM structures of MT1 and MT2 were reported.

Aralkylamine <i>N</i>-acetyltransferase Class of enzymes

Aralkylamine N-acetyltransferase (AANAT), also known as arylalkylamine N-acetyltransferase or serotonin N-acetyltransferase (SNAT), is an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. It is in humans encoded by the ~2.5 kb AANAT gene containing four exons, located on chromosome 17q25. The gene is translated into a 23 kDa large enzyme. It is well conserved through evolution and the human form of the protein is 80 percent identical to sheep and rat AANAT. It is an acetyl-CoA-dependent enzyme of the GCN5-related family of N-acetyltransferases (GNATs). It may contribute to multifactorial genetic diseases such as altered behavior in sleep/wake cycle and research is on-going with the aim of developing drugs that regulate AANAT function.

<span class="mw-page-title-main">Acetylserotonin O-methyltransferase</span> Mammalian protein found in humans

N-Acetylserotonin O-methyltransferase, also known as ASMT, is an enzyme which catalyzes the final reaction in melatonin biosynthesis: converting Normelatonin to melatonin. This reaction is embedded in the more general tryptophan metabolism pathway. The enzyme also catalyzes a second reaction in tryptophan metabolism: the conversion of 5-hydroxy-indoleacetate to 5-methoxy-indoleacetate. The other enzyme which catalyzes this reaction is n-acetylserotonin-o-methyltransferase-like-protein.

5-HT<sub>1A</sub> receptor Serotonin receptor protein distributed in the cerebrum and raphe nucleus

The serotonin 1A receptor is a subtype of serotonin receptors, or 5-HT receptors, that binds serotonin, also known as 5-HT, a neurotransmitter. 5-HT1A is expressed in the brain, spleen, and neonatal kidney. It is a G protein-coupled receptor (GPCR), coupled to the Gi protein, and its activation in the brain mediates hyperpolarization and reduction of firing rate of the postsynaptic neuron. In humans, the serotonin 1A receptor is encoded by the HTR1A gene.

<span class="mw-page-title-main">Luzindole</span> Chemical compound

Luzindole (N-0774), (N-acetyl-2-benzyltryptamine), is a drug used in scientific research to study the role of melatonin in the body. Luzindole acts as a selective melatonin receptor antagonist, with approximately 11- to 25-fold greater affinity for the MT2 over the MT1 receptor. In animal studies, it has been observed to disrupt the circadian rhythm as well as produce antidepressant effects.

A serotonin modulator and stimulator (SMS), sometimes referred to more simply as a serotonin modulator, is a type of drug with a multimodal action specific to the serotonin neurotransmitter system. To be precise, SMSs simultaneously modulate one or more serotonin receptors and inhibit the reuptake of serotonin. The term was created to describe the mechanism of action of the serotonergic antidepressant vortioxetine, which acts as a serotonin reuptake inhibitor (SRI), agonist of the 5-HT1A receptor, and antagonist of the 5-HT3 and 5-HT7 receptors. However, it can also technically be applied to vilazodone, which is an antidepressant as well and acts as an SRI and 5-HT1A receptor partial agonist.

<span class="mw-page-title-main">Piromelatine</span> Chemical compound

Piromelatine (Neu-P11) is a multimodal sleep drug under development by Neurim Pharmaceuticals. It is an agonist at melatonin MT1/MT2 and serotonin 5-HT1A/5-HT1D receptors. Neurim is conducting a phase II randomized, placebo controlled trial of cognitive and sleep effects in Alzheimer's disease.

<span class="mw-page-title-main">Tropoflavin</span> Chemical compound

Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves. It has been found to act as a potent and selective small-molecule agonist of the tropomyosin receptor kinase B (TrkB), the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF). Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier. A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13, is under development for the treatment of Alzheimer's disease.

<span class="mw-page-title-main">HIOC</span> Chemical compound

HIOC is a small-molecule agent which acts as a selective TrkB receptor agonist. It was derived from N-acetylserotonin (NAS). Relative to NAS, HIOC possesses greater potency and a longer half-life. It is described as producing long-lasting activation of the TrkB receptor and downstream signaling kinases associated with the receptor. HIOC is systemically-active and is able to penetrate the blood-brain-barrier. In animal studies, HIOC was found to robustly protect against glutamate-induced excitotoxicity, an action which was TrkB-dependent.

<span class="mw-page-title-main">6-Hydroxymelatonin</span> Chemical compound

6-Hydroxymelatonin (6-OHM) is a naturally occurring, endogenous, major active metabolite of melatonin. Similar to melatonin, 6-OHM is a full agonist of the MT1 and MT2 receptors. It is also an antioxidant and neuroprotective, and is even more potent in this regard relative to melatonin.

<span class="mw-page-title-main">ANA-12</span> Chemical compound

ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes and as long as 6 hours following intraperitoneal injection in mice. It blocks the neurotrophic actions of BDNF without compromising neuron survival.

<span class="mw-page-title-main">Melatonin as a medication and supplement</span> Supplement and medication used to treat sleep disorders

Melatonin is a dietary supplement and medication as well as naturally occurring hormone. As a hormone, melatonin is released by the pineal gland and is involved in sleep–wake cycles. As a supplement, it is often used for the attempted short-term treatment of disrupted sleep patterns, such as from jet lag or shift work, and is typically taken orally. Evidence of its benefit for this use, however, is not strong. A 2017 review found that sleep onset occurred six minutes faster with use, but found no change in total time asleep.

Gabriella Gobbi is an Italo-Canadian psychiatrist and neuroscientist whose research explores novel treatments for mental health disorders. Gobbi is a professor at McGill University's Department of Psychiatry and a Canada Research Chair in Therapeutics for Mental Health.

References

  1. ↑ AXELROD J, WEISSBACH H (April 1960). "Enzymatic O-methylation of N-acetylserotonin to melatonin". Science. 131 (3409): 1312. Bibcode:1960Sci...131.1312A. doi:10.1126/science.131.3409.1312. PMID   13795316. S2CID   22341451.
  2. ↑ WEISSBACH H, REDFIELD BG, AXELROD J (September 1960). "Biosynthesis of melatonin: enzymic conversion of serotonin to N-acetylserotonin". Biochimica et Biophysica Acta. 43: 352–3. doi:10.1016/0006-3002(60)90453-4. PMID   13784117.
  3. 1 2 3 4 5 6 7 Jang SW, Liu X, Pradoldej S, et al. (February 2010). "N-acetylserotonin activates TrkB receptor in a circadian rhythm". Proceedings of the National Academy of Sciences of the United States of America. 107 (8): 3876–81. Bibcode:2010PNAS..107.3876J. doi: 10.1073/pnas.0912531107 . PMC   2840510 . PMID   20133677.
  4. ↑ Zhao H, Poon AM, Pang SF (March 2000). "Pharmacological characterization, molecular subtyping, and autoradiographic localization of putative melatonin receptors in uterine endometrium of estrous rats". Life Sciences. 66 (17): 1581–91. doi:10.1016/S0024-3205(00)00478-1. PMID   11261588.
  5. ↑ Nonno R, Pannacci M, Lucini V, Angeloni D, Fraschini F, Stankov BM (July 1999). "Ligand efficacy and potency at recombinant human MT2 melatonin receptors: evidence for agonist activity of some mt1-antagonists". British Journal of Pharmacology . 127 (5): 1288–94. doi:10.1038/sj.bjp.0702658. PMC   1566130 . PMID   10455277.
  6. ↑ Paul P, Lahaye C, Delagrange P, Nicolas JP, Canet E, Boutin JA (July 1999). "Characterization of 2-[125I]iodomelatonin binding sites in Syrian hamster peripheral organs". The Journal of Pharmacology and Experimental Therapeutics. 290 (1): 334–40. PMID   10381796.
  7. 1 2 Tosini G., Ye K. & Iuvone PM (2012). "Neuroprotection, neurogenesis, and the sleepy brain". Neuroscientist. 18 (6): 645–653. doi:10.1177/1073858412446634. PMC   3422380 . PMID   22585341.
  8. 1 2 Oxenkrug G. & Ratner R. (2012). "N-acetylserotonin and aging-associated cognitive impairment and depression". Aging Dis. 3 (4): 330–338. PMC   3501368 . PMID   23185714.
  9. 1 2 Sompol P.; Liu X.; Baba K.; Paul KN.; Tosini G.; Iuvone PM.; Ye K. (2011). "N-acetylserotonin promotes hippocampal neuroprogenitor cell proliferation in sleep-deprived mice". Proc. Natl. Acad. Sci. U.S.A. 108 (21): 8844–9. Bibcode:2011PNAS..108.8844S. doi: 10.1073/pnas.1105114108 . PMC   3102377 . PMID   21555574.
  10. ↑ Oxenkrug G (2005). "Antioxidant effects of N-acetylserotonin: possible mechanisms and clinical implications". Ann. N. Y. Acad. Sci. 1053: 334–47. doi:10.1111/j.1749-6632.2005.tb00042.x. PMID   16179540. S2CID   94273958.
  11. ↑ Gavazza MB.; Català A. (2004). "Protective effect of N-acetyl-serotonin on the nonenzymatic lipid peroxidation in rat testicular microsomes and mitochondria". J. Pineal Res. 37 (3): 153–60. doi:10.1111/j.1600-079x.2004.00150.x. PMID   15357659. S2CID   6974587.
  12. ↑ Wölfler A.; Abuja PM.; Schauenstein K.; Liebmann PM. (1999). "N-acetylserotonin is a better extra- and intracellular antioxidant than melatonin". FEBS Lett. 449 (2–3): 206–10. doi:10.1016/s0014-5793(99)00435-4. PMID   10338133. S2CID   32077728.
  13. ↑ Peter Klemm; Markus Hecker; Hannelore Stockhausen; Chin Chen Wu; Christoph Thiemermann (Aug 1995). "Inhibition by N-acetyl-5-hydroxytryptamine of nitric oxide synthase expression in cultured cells and in the anaesthetized rat". Br J Pharmacol. 115 (7): 1175–1181. doi:10.1111/j.1476-5381.1995.tb15021.x. PMC   1908794 . PMID   7582541.
  14. ↑ Perianayagam MC.; Oxenkrug GF.; Jaber BL. (2005). "Immune-modulating effects of melatonin, N-acetylserotonin, and N-acetyldopamine". Ann. N. Y. Acad. Sci. 1053: 386–93. doi:10.1111/j.1749-6632.2005.tb00046.x. PMID   16179544. S2CID   592935.
  15. 1 2 3 Oxenkrug GF (1999). "Antidepressive and antihypertensive effects of MAO-A inhibition: role of N-acetylserotonin. A review". Neurobiology (Budapest, Hungary). 7 (2): 213–24. PMID   10591054.
  16. 1 2 Oxenkrug GF (1997). "[N-acetylserotonin and hypotensive effect of MAO-A inhibitors]". Voprosy Meditsinskoi Khimii (in Russian). 43 (6): 522–6. PMID   9503569.
  17. ↑ "N-Acetyl Serotonin". DrugBank.