NMDA Receptor
Traxoprodil is a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. [2]

（1S，2S）-1-（4-羟基苯基）-2-（4-羟基-4-苯基哌啶基）-1-丙醇（20，CP-101606）是一种有效的选择性N-甲基-D-天冬氨酸（NMDA）拮抗剂。本报告中探索的苏二烷基骨架上的位点包括侧基甲基（H、甲基和乙基几乎相等；丙基弱得多）、连接C-4苯基和哌啶环的间隔基（一种具有0和2个碳原子的交替效力模式，产生最大效力）和简单的苯基取代（影响很小）。虽然通过双原子间隔物获得了强效的NMDA拮抗剂，但这种排列也增加了α1肾上腺素能亲和力。在这些哌啶环的C-4位置引入羟基导致α1肾上腺素能亲和力大幅降低。这些观察结果的结合对20的发现起到了重要作用。该化合物能有效保护培养的海马神经元免受谷氨酸毒性（IC50=10 nM），同时几乎不具有伊芬普利不希望的α1肾上腺素能亲和力（IC50约为20微M）。此外，20似乎缺乏非选择性竞争性和通道阻断性NMDA拮抗剂的精神运动兴奋作用。因此，20显示出作为神经保护剂的巨大前景，并且可能缺乏目前临床试验中化合物的副作用[1]。

Traxoprodil (20 nM icv) 增加 PTZ (70 mg/kg; ip) 诱导的全身强直破伤风； Traxoprodil（60 mg/kg，煤）延长了强直恢复和饱腹感的潜在时间，并减少了总预期受益时间[3]。 Traxoprodil 在 20 和 40 mg/kg 剂量的强迫游泳试验中表现出抗抑郁活性，并且与动物运动的变化相关 [2]。

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多胺，包括亚精胺，通过积极调节N-甲基-d-天冬氨酸受体（NMDAr）促进癫痫发作。尽管NMDAr拮抗剂可以减少癫痫发作，但仍有待确定的是，NMDAr NR2B亚基的选择性拮抗剂曲索地尔是否会减少癫痫发作以及亚精胺是否会促进戊四唑（PTZ）诱导的癫痫发作。成年雄性Wistar大鼠侧脑室注射0.9%氯化钠（1μl，i.c.v.）、亚精胺（0.02、0.2或2nmol/位点，i.c.v）或曲索地尔（0.2、2或20nmol，i.c.v.）和PTZ（35或70mg/kg，i.p.）。还研究了口服曲索地尔（60mg/kg，口服）对癫痫发作的影响。通过行为和电图方法（EEG）记录阵挛性和全身性癫痫发作的潜伏期以及癫痫发作的总时间。亚精胺（2nmol/位点；i.c.v.）有助于亚阈值剂量的PTZ（35mg/kg；i.p.）诱导的癫痫发作，但不会改变抽搐剂量PTZ（70mg/kg；i.p..）诱导的发作活动。Traxoprodil（20nmol i.c.v.）增加了PTZ（70mg/kg；i.p.）诱导的全身强直-阵挛发作的潜伏期。Traxoprodil（60mg/kg，口服）增加了阵挛性和全身性癫痫发作的潜伏期，并减少了癫痫发作的总时间。这些结果支持NR2B亚基在PTZ诱导的癫痫发作中的作用。[2]

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在小鼠强迫游泳实验中，以 20 和 40 mg/kg 剂量给药的 Traxoprodil 能显著缩短总不动时间，表现出抗抑郁样活性。5 和 10 mg/kg 剂量无效。[2]
血清素合成抑制剂对氯苯丙氨酸（p-CPA）预处理能部分逆转 20 mg/kg Traxoprodil 的抗抑郁样作用，提示血清素系统部分参与其作用。[2]
将无效剂量的 Traxoprodil (10 mg/kg) 与亚治疗剂量的丙咪嗪 (15 mg/kg)、氟西汀 (5 mg/kg) 或艾司西酞普兰 (2 mg/kg) 联用，能显著缩短强迫游泳实验中的不动时间，表明其能增强这些药物的抗抑郁效果。[2]
将 Traxoprodil (10 mg/kg) 与瑞波西汀 (2.5 mg/kg) 联用未产生显著的不动时间缩短。[2]
用选择性 5-HT_1A 受体拮抗剂 WAY 100,635 (0.1 mg/kg) 或选择性 5-HT₂ 受体拮抗剂利坦色林 (4 mg/kg) 预处理，均不能逆转 20 mg/kg Traxoprodil 在强迫游泳实验中的抗抑郁样作用。[2]
在所有测试剂量 (5, 10, 20, 40 mg/kg) 下，Traxoprodil 均未显著影响小鼠的自发 locomotor 活动，表明其在强迫游泳实验中的行为效应并非由于兴奋作用。[2]
Traxoprodil 与丙咪嗪、氟西汀、艾司西酞普兰、瑞波西汀，以及与 p-CPA、WAY 100,635 或利坦色林联用，均未显著影响 locomotor 活动。[2]

Traxoprodil (5, 10, 20, and 40 mg/kg) was suspended in a 1 % aqueous solution of Tween 80 (POCH), whereas imipramine hydrochloride (15 and 30 mg/kg), fluoxetine hydrochloride (5 mg/kg), escitalopram oxalate (2 mg/kg), reboxetine mesylate (2.5 mg/kg), WAY 100,635 (0.1 mg/kg), and ritanserin (4 mg/kgh) were dissolved in physiological saline (0.9 % NaCl). The solutions/suspension were prepared immediately prior to the experiments and were administered intraperitoneally (i.p.) 60 min before testing. The doses and pretreatment schedules were selected on the basis of the literature data and the results of our previous experiments (Poleszak et al. 2005, 2007a, 2011, 2013; Szewczyk et al. 2002, 2009). Animals from the control groups received i.p. injections of the vehicle (saline). The volume of all administered solutions/suspension was 10 ml/kg.[2]

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Adult male Albino Swiss mice (25-30 g) were used. Traxoprodil was suspended in a 1% aqueous solution of Tween 80. Imipramine hydrochloride, fluoxetine hydrochloride, escitalopram oxalate, reboxetine mesylate, WAY 100,635, and ritanserin were dissolved in physiological saline (0.9% NaCl). All drugs were administered intraperitoneally (i.p.) in a volume of 10 ml/kg, 60 minutes before behavioral testing. [2]
For the forced swim test, each mouse was placed in a glass cylinder containing water (23-25°C) for 6 minutes, and the total immobility time during the last 4 minutes was recorded. [2]
For locomotor activity assessment, animals were placed in activity chambers, and the distance traveled was recorded between the 2nd and 6th minutes. [2]
For serotonergic lesion, p-chlorophenylalanine (p-CPA) was dissolved in saline and administered i.p. at 200 mg/kg for 3 consecutive days. On the fourth day, mice were given traxoprodil (20 mg/kg) or saline 60 minutes before the FST. [2]
For pharmacokinetic studies, drugs were administered i.p., and mice were decapitated 60 minutes later. Brains were collected, weighed, homogenized in buffer, and drug concentrations were determined using HPLC with fluorescence detection. [2]

Metabolism/Metabolites
The known metabolites of trosoprodil include 4-[1-hydroxy-2-(4-hydroxy-4-phenylpiperidin-1-yl)propyl]phenyl-1,2-diol.

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Combined administration of trosoprodil (10 mg/kg) with imipramine (15 mg/kg) significantly increased the concentrations of imipramine and its metabolite desipramine in the brain compared with imipramine alone. [2]
Combined administration of trosoprodil (10 mg/kg) with escitalopram (2 mg/kg) significantly increased the concentrations of escitalopram and trosoprodil in the brain compared with imipramine alone. [2]
Combined administration of trosoprodil (10 mg/kg) with fluoxetine (5 mg/kg) did not significantly alter the brain concentration of fluoxetine, but significantly increased the brain concentration of trosoprodil compared with trosoprodil alone. [2]
Combination administration of trisoprodil (10 mg/kg) with imipramine (15 mg/kg) did not significantly alter the brain concentration of trisoprodil. [2]

[1]. (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem. 1995 Aug 4;38(16):3138-45.

[2]. Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice. Metab Brain Dis. 2016 Aug;31(4):803-14.

[3]. Traxoprodil decreases pentylenetetrazol-induced seizures. Epilepsy Res. 2012 Jun;100(1-2):12-9.

Metabolism / Metabolites:
Known human metabolites of trosoprodil include 4-[1-hydroxy-2-(4-hydroxy-4-phenylpiperidin-1-yl)propyl]phenyl-1,2-diol.

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Trosoprodil is one of the most recently discovered substances with antidepressant activity; it is a selective antagonist of the NMDA receptor NR2B subunit. The primary objective of this study was to evaluate the effects of trosoprodil on animal behavior using a forced swimming test (FST), and the effects of trosoprodil (10 mg/kg) on the activity of antidepressants such as imipramine (15 mg/kg), fluoxetine (5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). To assess the role of the serotonergic system in the antidepressant effect of trosoprodil, we performed a serotonergic impairment assay using selective serotonergic receptor agonists of 5-HT1A and 5-HT2. The concentrations of the test drug in the brain were determined using high-performance liquid chromatography (HPLC). Results showed that trosoprodil exhibited antidepressant activity at doses of 20 and 40 mg/kg, independent of changes in animal motor activity. Co-administration of trosoprodil with subtherapeutic doses of imipramine, fluoxetine, or escitalopram significantly affected animal behavior in the forced swimming test (FST), and importantly, these changes were not related to the severity of motor activity. The observed trosoprodil effects were only partially related to the serotonergic system and were independent of effects on 5-HT1A and 5-HT2 serotonin receptors. An attempt to assess the interaction properties of trosoprodil with the test drug indicated that an interaction exists at the pharmacokinetic stage when trosoprodil is co-administered with fluoxetine, imipramine, or escitalopram. [2]

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Trosoprotidel antagonizes the activity of NR1/NR2B NMDA receptor channels by shortening their opening time and frequency, thereby preventing excessive calcium influx into neurons. [2]
Its binding sites are mainly located in the forebrain, hippocampus, and extracortical layer. [2]
It is an analogue of isofenprodil, but has no activity against α1-adrenergic receptors. [2]
Its antidepressant-like mechanism of action is only partially related to the serotonergic system and is independent of the regulation of 5-HT1A and 5-HT2 receptors. [2]
The interaction between trosoprodil and the tested antidepressants (imipramine, fluoxetine, escitalopram) appears to be pharmacokinetic in nature, as evidenced by changes in intracerebral drug concentrations. [2]
Trosoprotidel is metabolized through the cytochrome P450 system and can affect the activity of CYP2D6 isoenzymes. [2]

C20H25NO3

327.4174

327.183

C, 73.37; H, 7.70; N, 4.28; O, 14.66

134234-12-1

Traxoprodil mesylate;188591-67-5

219101

White to off-white solid powder

1.2±0.1 g/cm3

534.4±50.0 °C at 760 mmHg

290.3±28.8 °C

0.0±1.5 mmHg at 25°C

1.626

1.75

63.93

3

4

4

24

380

2

C[C@@H]([C@H](C1=CC=C(C=C1)O)O)N2CCC(CC2)(C3=CC=CC=C3)O

QEMSVZNTSXPFJA-HNAYVOBHSA-N

InChI=1S/C20H25NO3/c1-15(19(23)16-7-9-18(22)10-8-16)21-13-11-20(24,12-14-21)17-5-3-2-4-6-17/h2-10,15,19,22-24H,11-14H2,1H3/t15-,19+/m0/s1

1-((1S,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-4-phenylpiperidin-4-ol

CP-101606; CP-98113; CP101606; 1-((1S,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-4-phenylpiperidin-4-ol; CP-101,606; Traxoprodil [INN]; CP98113; CP 101606; CP101,606; CP 98113.

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 : ~62.5 mg/mL (~190.89 mM)
H2O : ~0.1 mg/mL (~0.31 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (6.35 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 20.8 mg/mL澄清DMSO储备液加入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 (6.35 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 (6.35 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;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。