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| Targets |
N-Acetyl-5-hydroxytryptamine (NAS) is a potent and specific agonist of the tropomyosin receptor kinase B (TrkB) receptor. It activates TrkB in a neurotrophin (e.g., BDNF)-independent and MT3 receptor-independent manner. [1]
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| ln Vitro |
N-Acetyl-5-hydroxytryptamine (NAS) is the precursor of melatonin, which arylalkylamine N-acetyltransferase, or AANAT, acetylates. In a circadian rhythm, N-acetyl serotonin activates TrkB receptors. N-acetyl-5-hydroxytryptamine has antidepressant effects that are TrkB-dependent and quickly activate TrkB in a circadian manner. TrkB is quickly activated by N-acetyl-serotonin, but not TrkA or TrkC. This process is independent of neurotrophin and the MT3 receptor [1].
Treatment of primary cortical neurons with NAS (as low as 50 nM) induces rapid phosphorylation (activation) of TrkB, but not TrkA or TrkC, in a dose-dependent and time-dependent manner (detectable at 10 min, peaking at 30 min). This activation is blocked by the Trk receptor inhibitor K252a. [1] NAS (100 nM) also activates downstream signaling pathways of TrkB, including phosphorylation of Akt and extracellular signal-regulated kinase 1/2 (Erk1/2), in primary cortical neurons. [1] NAS prevents glutamate-induced apoptosis in primary neurons in a dose-dependent manner. [1] The activation of TrkB by NAS occurs in cortical neurons derived from BDNF-null mice, and is not blocked by neutralizing antibodies against BDNF, NT-3, or NT-4, confirming its action is independent of neurotrophins. [1] The activation of TrkB by NAS is not mediated by the MT3 melatonin receptor binding site, as pre-treatment with MT3 antagonists (prazosin, N-acetyltryptamine) or an agonist (5-MCA-NAT) does not affect NAS-induced TrkB phosphorylation. [1] NAS specifically activates TrkB in neurons from wild-type mice but not in neurons from TrkB-null mice, confirming receptor specificity. It also activates a TrkB F616A mutant receptor, and this activation is selectively blocked by the kinase inhibitor 1NMPP1. [1] |
| ln Vivo |
TrkB F616A knock-in mice were utilized to investigate whether N-acetyl-serotonin may cause TrkB activation in vivo. The findings demonstrated that 1NMPP1, a derivative of the kinase inhibitor PP1, could selectively block TrkB F616A activation, leading to a TrkB null phenotype. Mice with TrkB F616A knock-in mice were used to prepare cortical neurons in order to test the ability of N-acetyl-serotonin to mimic BDNF. In line with earlier findings, 1NMPP1 but not K252a selectively decreased TrkB phosphorylation, while melatonin or serotonin had no effect. These results show that NAS significantly increases the tyrosine phosphorylation and activation of wild-type TrkB and TrkB F616A [1].
Intraperitoneal administration of NAS (20 mg/kg) activates TrkB (induces phosphorylation) in the hippocampus and retina of BDNF forebrain conditional knockout mice within 0.5 to 1 hour, whereas melatonin (1 mg/kg) has no effect. [1] Endogenous TrkB activation in the retina of wild-type C3H/f+/+ mice follows a circadian rhythm, with high phosphorylation levels during the subjective night and low levels during the subjective morning. This circadian activation pattern is absent in AANAT-mutant C57BL/6J mice, which have impaired NAS synthesis. [1] In the forced swim test, NAS (20 mg/kg, i.p., administered 1 hour before test) significantly reduces immobility time in C57BL/6J mice compared to saline control, demonstrating an antidepressant-like effect. Melatonin (1 mg/kg) has no significant effect. [1] The antidepressant-like effect of NAS is TrkB-dependent, as pre-treatment with the TrkB F616A-specific inhibitor 1NMPP1 abolishes the reduction in immobility time induced by NAS in TrkB F616A mutant mice. [1] NAS (20 mg/kg, i.p.) suppresses kainic acid (KA)-induced neuronal apoptosis (measured by caspase-3 activation) in TrkB F616A mutant mice. This neuroprotective effect is blocked by pre-treatment with 1NMPP1, confirming TrkB-dependence. [1] |
| Animal Protocol |
In vivo TrkB activation studies: NAS was dissolved in normal saline containing 1% Tween-20. Mice (C3H/f+/+, C57BL/6J, BDNF conditional knockouts, TrkB F616A mutants) received a single intraperitoneal (i.p.) injection of NAS at a dose of 20 mg/kg. Control mice received vehicle or melatonin (1 mg/kg, i.p.). Mice were euthanized at specified time points (0.5, 1, 2 hours) after injection, and brain regions (hippocampus) or retina were rapidly dissected and frozen for immunoblot analysis. [1]
Neuroprotection study (KA model): TrkB F616A mice were pre-treated with 1NMPP1 (50 μM in drinking water) or water for one day. Then, mice received an i.p. injection of NAS (20 mg/kg) or melatonin (1 mg/kg). One hour later, mice were injected with kainic acid (KA, 20 mg/kg, i.p.). Brain lysates were prepared 4 hours after KA treatment for caspase-3 analysis. [1] Forced swim test (antidepressant effect): Adult male mice (C57BL/6J or TrkB F616A mutants) received a single i.p. injection of NAS (20 mg/kg, in saline with 1% Tween-20) or vehicle 1 hour before the behavioral test. For TrkB-dependency testing, TrkB F616A mice were pre-treated with 1NMPP1 in drinking water for 2 days prior to NAS administration. Immobility time was recorded during the last 4 minutes of a 6-minute forced swim session. [1] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites
Known metabolites of N-acetyl-5-hydroxytryptamine include (2S,3S,4S,5R)-6-[[3-(2-acetaminoethyl)-1H-indole-5-yl]oxy]-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid and 3-(2-acetaminoethyl)-1H-indole-5-yl hydrogen sulfate. N-acetyl-5-hydroxytryptamine is a known metabolite of melatonin. |
| References | |
| Additional Infomation |
N-acetylserotonin is an N-acylserotonin formed by the condensation of the primary amino group of serotonin with the carboxyl group of acetic acid. It is a human metabolite, a mouse metabolite, an antioxidant, and a tropomyosin-associated kinase B receptor agonist. It belongs to the acetamide, phenol, and N-acylserotonin classes of compounds. N-acetyl-5-hydroxytryptamine has been reported in Daphnia pulex, Drosophila melanogaster, and other organisms with relevant data. N-acetylserotonin is a natural intermediate in the endogenous synthesis of melatonin from serotonin. N-acetylserotonin (NAS) binds to and activates the melatonin receptor and the brain-derived neurotrophic factor/neurotrophic factor-3 (BDNF/NT-3) growth factor receptor (NTRK2; TrkB). NAS-dependent melatonin receptor signaling may improve age-related cognitive decline and depression, while the binding of NAS to TrkB may induce neural progenitor cell proliferation, thereby producing antidepressant and neurotrophic effects.
N-acetyl-5-hydroxytryptamine (NAS) is an endogenous serotonin metabolite and a direct precursor of melatonin, synthesized by arylalkylamine N-acetyltransferase (AANAT). Its synthesis and levels exhibit a distinct circadian rhythm. [1] This study found that NAS is a novel, endogenous, circadian-regulated TrkB receptor agonist, distinct from brain-derived neurotrophic factor (BDNF). Its activation of TrkB is the basis for the observed neuroprotective and antidepressant-like effects. [1] The results suggest that NAS may mediate part of the therapeutic effects of certain antidepressants (e.g., MAO-A inhibitors such as clogiline), which increase its endogenous levels, and its TrkB-dependent effects provide a molecular mechanism for its physiological function. [1] |
| Molecular Formula |
C12H14N2O2
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|---|---|
| Molecular Weight |
218.2518
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| Exact Mass |
218.105
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| CAS # |
1210-83-9
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| Related CAS # |
N-Acetyl-5-hydroxytryptamine-d3;2001098-07-1
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| PubChem CID |
903
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| Appearance |
Off-white to light brown solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
556.8±40.0 °C at 760 mmHg
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| Melting Point |
120-122 °C(lit.)
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| Flash Point |
290.6±27.3 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.651
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| LogP |
-0.13
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
16
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| Complexity |
257
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
MVAWJSIDNICKHF-UHFFFAOYSA-N
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| InChi Code |
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)
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| Chemical Name |
N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]acetamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~458.19 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (11.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (9.53 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (9.53 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 4.5819 mL | 22.9095 mL | 45.8190 mL | |
| 5 mM | 0.9164 mL | 4.5819 mL | 9.1638 mL | |
| 10 mM | 0.4582 mL | 2.2910 mL | 4.5819 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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