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]

N-乙酰基-5-羟色胺 (NAS) 是褪黑激素的前体，由芳基烷基胺 N-乙酰转移酶 (AANAT) 乙酰化。在昼夜节律中，N-乙酰血清素会激活 TrkB 受体。 N-乙酰基-5-羟色胺具有 TrkB 依赖性的抗抑郁作用，并以昼夜节律方式快速激活 TrkB。 TrkB 会被 N-乙酰血清素快速激活，但 TrkA 或 TrkC 不会被激活。该过程独立于神经营养素和 MT3 受体 [1]。

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用NAS（低至50 nM）处理原代皮层神经元，能以剂量依赖性和时间依赖性方式（10分钟可检测，30分钟达峰）快速诱导TrkB（而非TrkA或TrkC）的磷酸化（激活）。这种激活可被Trk受体抑制剂K252a阻断。 [1]
NAS (100 nM) 在原代皮层神经元中也激活TrkB的下游信号通路，包括Akt和细胞外信号调节激酶1/2 (Erk1/2)的磷酸化。 [1]
NAS 以剂量依赖性方式防止谷氨酸诱导的原代神经元凋亡。 [1]
NAS 对TrkB的激活发生在来源于BDNF敲除小鼠的皮层神经元中，并且不受抗BDNF、NT-3或NT-4的中和抗体阻断，证实其作用不依赖于神经营养因子。 [1]
NAS 对TrkB的激活不是由MT3褪黑素受体结合位点介导的，因为用MT3拮抗剂（哌唑嗪、N-乙酰色胺）或激动剂（5-MCA-NAT）预处理不影响NAS诱导的TrkB磷酸化。 [1]
NAS 特异性激活野生型小鼠神经元中的TrkB，而在TrkB敲除小鼠的神经元中则无此作用，证实了受体特异性。它也能激活TrkB F616A突变受体，且该激活可被激酶抑制剂1NMPP1选择性阻断。 [1]

利用 TrkB F616A 敲入小鼠来研究 N-乙酰基血清素是否可能导致体内 TrkB 激活。研究结果表明，激酶抑制剂 PP1 的衍生物 1NMPP1 可以选择性阻断 TrkB F616A 激活，从而导致 TrkB 无效表型。使用 TrkB F616A 敲入小鼠来制备皮质神经元，以测试 N-乙酰血清素模拟 BDNF 的能力。与早期的研究结果一致，1NMPP1（而非 K252a）选择性降低 TrkB 磷酸化，而褪黑素或血清素则没有效果。这些结果表明，NAS 显着增加了野生型 TrkB 和 TrkB F616A 的酪氨酸磷酸化和激活 [1]。

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腹腔注射NAS (20 mg/kg) 可在0.5至1小时内在BDNF前脑条件性敲除小鼠的海马和视网膜中激活TrkB（诱导磷酸化），而褪黑素 (1 mg/kg) 无效。 [1]
野生型C3H/f^+/+小鼠视网膜中的内源性TrkB激活遵循昼夜节律，在主观夜间磷酸化水平高，在主观早晨水平低。这种节律性激活模式在NAS合成受损的AANAT突变型C57BL/6J小鼠中缺失。 [1]
在强迫游泳实验中，与生理盐水对照组相比，NAS (20 mg/kg，腹腔注射，测试前1小时给药) 显著减少C57BL/6J小鼠的不动时间，显示出抗抑郁样作用。褪黑素 (1 mg/kg) 无显著作用。 [1]
NAS 的抗抑郁样作用是TrkB依赖性的，因为用TrkB F616A特异性抑制剂1NMPP1预处理，可消除NAS在TrkB F616A突变小鼠中诱导的不动时间减少。 [1]
NAS (20 mg/kg，腹腔注射) 抑制红藻氨酸 (KA) 诱导的TrkB F616A突变小鼠神经元凋亡（通过caspase-3激活测量）。这种神经保护作用可被1NMPP1预处理阻断，证实了TrkB依赖性。 [1]

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]

Metabolism / Metabolites
N-Acetyl-5-hydroxytryptamine has known human metabolites that include (2S,3S,4S,5R)-6-[[3-(2-acetamidoethyl)-1H-indol-5-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid and 3-(2-Acetamidoethyl)-1H-indol-5-yl hydrogen sulfate.
N-Acetyl-5-hydroxytryptamine is a known human metabolite of melatonin.

[1]. N-acetylserotonin activates TrkB receptor in a circadian rhythm. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3876-81.

N-acetylserotonin is an N-acylserotonin resulting from the formal condensation of the primary amino group of serotonin with the carboxy group of acetic acid. It has a role as a human metabolite, a mouse metabolite, an antioxidant and a tropomyosin-related kinase B receptor agonist. It is a member of acetamides, a member of phenols and a N-acylserotonin.
N-Acetyl-5-hydroxytryptamine has been reported in Daphnia pulex, Drosophila melanogaster, and other organisms with data available.
N-Acetylserotonin is a naturally occurring intermediate in the endogenous production of melatonin from serotonin. N-acetylserotonin (NAS) binds to and activates both melatonin receptors and BDNF/NT-3 growth factors receptor (NTRK2; TrkB). NAS-dependent melatonin receptor signaling may ameliorate aging-associated cognitive decline and depression, while NAS binding to TrkB may induce proliferation of neural progenitor cells, which may elicit anti-depressant and neurotrophic effects.

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N-Acetyl-5-hydroxytryptamine (NAS) is an endogenous serotonin metabolite and the immediate precursor of melatonin, synthesized by the enzyme arylalkylamine N-acetyltransferase (AANAT). Its synthesis and levels exhibit a clear circadian rhythm. [1]
This study identifies NAS as a novel, endogenous, circadian-regulated agonist of the TrkB receptor, distinct from brain-derived neurotrophic factor (BDNF). Its TrkB activation underlies observed neuroprotective and antidepressant-like effects. [1]
The findings suggest that NAS may mediate some of the therapeutic effects of certain antidepressants (e.g., MAO-A inhibitors like clorgyline) that increase its endogenous levels, and that its TrkB-dependent action provides a molecular mechanism for its physiological roles. [1]

C12H14N2O2

218.2518

218.105

1210-83-9

N-Acetyl-5-hydroxytryptamine-d3;2001098-07-1

903

Off-white to light brown solid powder

1.3±0.1 g/cm3

556.8±40.0 °C at 760 mmHg

120-122 °C(lit.)

290.6±27.3 °C

0.0±1.6 mmHg at 25°C

1.651

-0.13

65.12

3

2

3

16

257

0

MVAWJSIDNICKHF-UHFFFAOYSA-N

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)

N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]acetamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~458.19 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (11.45 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (9.53 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (9.53 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
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