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'''''N''-Acetylserotonin''' ('''NAS'''), also known as '''normelatonin''', is a [[natural product|naturally occurring]] [[chemical compound|chemical]] [[reaction intermediate|intermediate]] in the [[endogenous]] production of [[melatonin]] from [[serotonin]].<ref name="pmid13795316">{{cite journal | author = AXELROD J, WEISSBACH H | title = Enzymatic O-methylation of N-acetylserotonin to melatonin | journal = Science | volume = 131 | issue = 3409| page = 1312 |date=April 1960 | pmid = 13795316 | doi = 10.1126/science.131.3409.1312| url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=13795316}}</ref><ref name="pmid13784117">{{cite journal | author = WEISSBACH H, REDFIELD BG, AXELROD J | title = Biosynthesis of melatonin: enzymic conversion of serotonin to N-acetylserotonin | journal = Biochimica et Biophysica Acta | volume = 43 | issue = | pages = 352–3 |date=September 1960 | pmid = 13784117 | doi = 10.1016/0006-3002(60)90453-4| url = }}</ref> It is produced from serotonin by the [[enzyme]] [[aralkylamine N-acetyltransferase|aralkylamine ''N''-acetyltransferase]] (AANAT) and is converted to melatonin by [[Acetylserotonin O-methyltransferase|acetylserotonin ''O''-methyltransferase]] (ASMT). Like melatonin, NAS is an [[agonist]] at the [[melatonin receptor]]s [[MT1 receptor|MT<sub>1</sub>]], [[MT2 receptor|MT<sub>2</sub>]], and [[MT3 receptor|MT<sub>3</sub>]], and may be considered to be a [[neurotransmitter]].<ref name="pmid20133677">{{cite journal | author = Jang SW, Liu X, Pradoldej S, ''et al.'' | title = N-acetylserotonin activates TrkB receptor in a circadian rhythm | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107| issue = 8| pages = 3876|date=February 2010 | pmid = 20133677 | pmc = 2840510 | doi = 10.1073/pnas.0912531107 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=20133677}}</ref><ref name="pmid11261588">{{cite journal | author = Zhao H, Poon AM, Pang SF | title = Pharmacological characterization, molecular subtyping, and autoradiographic localization of putative melatonin receptors in uterine endometrium of estrous rats | journal = Life Sciences | volume = 66 | issue = 17 | pages = 1581–91 |date=March 2000 | pmid = 11261588 | doi = 10.1016/S0024-3205(00)00478-1| url = http://linkinghub.elsevier.com/retrieve/pii/S0024320500004781}}</ref><ref name="pmid10455277">{{cite journal | author = Nonno R, Pannacci M, Lucini V, Angeloni D, Fraschini F, Stankov BM | title = Ligand efficacy and potency at recombinant human MT2 melatonin receptors: evidence for agonist activity of some mt1-antagonists | journal = [[British Journal of Pharmacology]] | volume = 127 | issue = 5 | pages = 1288–94 |date=July 1999 | pmid = 10455277 | pmc = 1566130 | doi = 10.1038/sj.bjp.0702658 }}</ref><ref name="pmid10381796">{{cite journal | author = Paul P, Lahaye C, Delagrange P, Nicolas JP, Canet E, Boutin JA | title = Characterization of 2-[125I]iodomelatonin binding sites in Syrian hamster peripheral organs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 290 | issue = 1 | pages = 334–40 |date=July 1999 | pmid = 10381796 | doi = | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10381796}}</ref> 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 (biochemistry)|precursor]] in the [[synthesis (chemical)|synthesis]] of melatonin.<ref name="pmid20133677" />
'''''N''-Acetylserotonin''' ('''NAS'''), also known as '''normelatonin''', is a [[natural product|naturally occurring]] [[chemical compound|chemical]] [[reaction intermediate|intermediate]] in the [[endogenous]] production of [[melatonin]] from [[serotonin]].<ref name="pmid13795316">{{cite journal | author = AXELROD J, WEISSBACH H | title = Enzymatic O-methylation of N-acetylserotonin to melatonin | journal = Science | volume = 131 | issue = 3409| page = 1312 |date=April 1960 | pmid = 13795316 | doi = 10.1126/science.131.3409.1312| url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=13795316}}</ref><ref name="pmid13784117">{{cite journal | author = WEISSBACH H, REDFIELD BG, AXELROD J | title = Biosynthesis of melatonin: enzymic conversion of serotonin to N-acetylserotonin | journal = Biochimica et Biophysica Acta | volume = 43 | issue = | pages = 352–3 |date=September 1960 | pmid = 13784117 | doi = 10.1016/0006-3002(60)90453-4| url = }}</ref> It is produced from serotonin by the [[enzyme]] [[aralkylamine N-acetyltransferase|aralkylamine ''N''-acetyltransferase]] (AANAT) and is converted to melatonin by [[Acetylserotonin O-methyltransferase|acetylserotonin ''O''-methyltransferase]] (ASMT). Like melatonin, NAS is an [[agonist]] at the [[melatonin receptor]]s [[MT1 receptor|MT<sub>1</sub>]], [[MT2 receptor|MT<sub>2</sub>]], and [[MT3 receptor|MT<sub>3</sub>]], and may be considered to be a [[neurotransmitter]].<ref name="pmid20133677">{{cite journal | author = Jang SW, Liu X, Pradoldej S, ''et al.'' | title = N-acetylserotonin activates TrkB receptor in a circadian rhythm | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107| issue = 8| pages = 3876|date=February 2010 | pmid = 20133677 | pmc = 2840510 | doi = 10.1073/pnas.0912531107 | url = http://www.pnas.org/cgi/pmidlookup?view=long&pmid=20133677}}</ref><ref name="pmid11261588">{{cite journal | author = Zhao H, Poon AM, Pang SF | title = Pharmacological characterization, molecular subtyping, and autoradiographic localization of putative melatonin receptors in uterine endometrium of estrous rats | journal = Life Sciences | volume = 66 | issue = 17 | pages = 1581–91 |date=March 2000 | pmid = 11261588 | doi = 10.1016/S0024-3205(00)00478-1| url = http://linkinghub.elsevier.com/retrieve/pii/S0024320500004781}}</ref><ref name="pmid10455277">{{cite journal | author = Nonno R, Pannacci M, Lucini V, Angeloni D, Fraschini F, Stankov BM | title = Ligand efficacy and potency at recombinant human MT2 melatonin receptors: evidence for agonist activity of some mt1-antagonists | journal = [[British Journal of Pharmacology]] | volume = 127 | issue = 5 | pages = 1288–94 |date=July 1999 | pmid = 10455277 | pmc = 1566130 | doi = 10.1038/sj.bjp.0702658 }}</ref><ref name="pmid10381796">{{cite journal | author = Paul P, Lahaye C, Delagrange P, Nicolas JP, Canet E, Boutin JA | title = Characterization of 2-[125I]iodomelatonin binding sites in Syrian hamster peripheral organs | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 290 | issue = 1 | pages = 334–40 |date=July 1999 | pmid = 10381796 | doi = | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10381796}}</ref> 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 (biochemistry)|precursor]] in the [[synthesis (chemical)|synthesis]] of melatonin.<ref name="pmid20133677" /> NAS is able to penetrate the blood brain barrier, unlike serotonin.<ref>http://www.drugbank.ca/drugs/DB04275</ref>


Recently, NAS has been shown to act as a [[potency (pharmacology)|potent]] [[TrkB receptor]] agonist, while serotonin and melatonin are not.<ref name="pmid20133677" /> It produces robust [[antidepressant]], [[neuroprotective]], and [[neurotrophic]] effects that are TrkB-mediated.<ref name="pmid20133677" /> In addition, AANAT [[knockout mouse|knockout mice]] which lack NAS display significantly greater immobility times versus control mice in assays of [[major depressive disorder|depression]] like the [[forced swim test]].<ref name="pmid20133677" />
Recently, NAS has been shown to act as a [[potency (pharmacology)|potent]] [[TrkB receptor]] agonist, while serotonin and melatonin are not.<ref name="pmid20133677" /> It produces robust [[antidepressant]], [[neuroprotective]], and [[neurotrophic]] effects that are TrkB-mediated.<ref name="pmid20133677" /> In addition, AANAT [[knockout mouse|knockout mice]] which lack NAS display significantly greater immobility times versus control mice in assays of [[major depressive disorder|depression]] like the [[forced swim test]].<ref name="pmid20133677" />

Revision as of 15:57, 5 July 2014

N-Acetylserotonin
Names
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
ECHA InfoCard 100.013.560 Edit this at Wikidata
MeSH N-Acetylserotonin N-Acetylserotonin
  • 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) checkY
    Key: MVAWJSIDNICKHF-UHFFFAOYSA-N checkY
  • 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 218.252 g/mol
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).
☒N verify (what is checkY☒N ?)

N-Acetylserotonin (NAS), also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin.[1][2] It is produced from serotonin by the enzyme aralkylamine N-acetyltransferase (AANAT) and is converted to melatonin by acetylserotonin O-methyltransferase (ASMT). 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 able to penetrate the blood brain barrier, unlike serotonin.[7]

Recently, NAS has been shown to act as a potent TrkB receptor agonist, while serotonin and melatonin are not.[3] It produces robust antidepressant, neuroprotective, and neurotrophic effects that are TrkB-mediated.[3] In addition, AANAT knockout mice which lack NAS display significantly greater immobility times versus control mice in assays of depression like the forced swim test.[3]

NAS may also play a major 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][8] Furthermore, light exposure inhibits the synthesis of NAS and reduces the antidepressant effects of MAOIs.[3] These data strongly support a 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.[9][8] 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.[9][8] Why orthostatic hypotension is commonly seen with MAOIs but not SSRIs (both of which increase NAS levels) however, is unknown.

NAS is observed to inhibit nitric oxide synthase.[10][11]

See also

References

  1. ^ AXELROD J, WEISSBACH H (April 1960). "Enzymatic O-methylation of N-acetylserotonin to melatonin". Science. 131 (3409): 1312. doi:10.1126/science.131.3409.1312. PMID 13795316.
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ a b c d e f g h 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. doi:10.1073/pnas.0912531107. PMC 2840510. PMID 20133677. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ http://www.drugbank.ca/drugs/DB04275
  8. ^ a b c 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.
  9. ^ a b Oxenkrug GF (1997). "[N-acetylserotonin and hypotensive effect of MAO-A inhibitors]". Voprosy Meditsinskoi Khimii (in Russian). 43 (6): 522–6. PMID 9503569.
  10. ^ http://www.ncbi.nlm.nih.gov/pubmed/7582541
  11. ^ http://onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.1995.tb15021.x/pdf


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