Tryptophan hydroxylase

Fenclonine/PCPA诱导失眠大鼠模型的建立[4]
雄性SD大鼠（每组12只）被分配到六组中的一组。三组连续7天口服KL（4 g/kg、8 g/kg、12 g/kg），然后在第4天腹腔注射Fenclonine/PCPA（300 mg/kg），持续三天。两组分别接受口服生理盐水（对照组）和丁螺环酮（阳性组），然后在第4天腹腔注射Fenclonine/PCPA（300mg/kg），持续三天。一组作为空白组给予生理盐水。KL的剂量转换为原始植物的质量。治疗后第3天进行FST和TST的准备训练。最后，在第6天测量FST和TST不动时间。治疗7天后，将大鼠麻醉并通过颈椎脱位处死，取出大脑并立即置于冰上。
致病原理[4]
Fenclonine/PCPA可以抑制5-羟色胺 (5-HT) 的合成，诱导5-HT耗竭，导致失眠。

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用Fenclonine/PCPA治疗（腹腔注射；100 mg/kg；每天一次；3 天）可抑制吗啡诱导的镇痛活性[2]。用Fenclonine/PCPA预处理（腹腔注射；300 mg/kg；每天一次；3 天）后，剂量为 50 mg/kg 的扑热息痛被完全消除。

Animal/Disease Models: Wistar albino rats, either male or female, weighing 80 to 100 grams [2]
Doses: 100 mg/kg
Route of Administration: intraperitoneal (ip) injection; intraperitoneal (ip) injection. 100 mg/kg; one time/day; 3 days.
Experimental Results: Inhibited the analgesic activity of morphine by 41.5%.

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Animal/Disease Models: Male Swiss mouse (22-25 g) [3]
Doses: 300 mg/kg
Route of Administration: intraperitoneal (ip) injection; 300 mg/kg; one time/day; 3 days
Experimental Results: Inhibition of paracetamol on depressive-like and obsessive-compulsive behaviors Impact.

Absorption, Distribution and Excretion
6- Fluorotryptophan (6-FT) and p-chlorophenylalanine (pCPA) were given orally to six (mean weight 5.3 kg) and five (mean weight 7.5 kg) monkeys respectively maintained on a controlled diet. Plasma amino acid concentrations were estimated using an amino acid analyser, and in the 6-FT studies free tryptophan was determined by equilibrium dialysis. At least 3 weeks separated each ingestion. The drugs were given in marzipan at 0900 hr on each occasion. With 10, 30 and 100 mg/kg 6-FT the mean peak plasma levels of 6-FT were 24, 58 and 145 n mole/mL respectively, and each peak was observed at 11.00 hours. With pCPA (10 and 100 mg/kg) the mean peak plasma levels of pCPA were 59 and 343 n mole/mL, and peaks were observed at 1100 and 1300 hr respectively. It was not possible to measure the plasma levels after ingestion of pCPA (1 mg/kg). The plasma half times for 6-FT and pCPA were about 3.5 and 10.5 hours. In control studies plasma concentrations of tryptophan increased during the day, and reached their maximum during the afternoon. The increases in the plasma concentration at 1300 and 1700 hr were highly significant (P<0.01). Oral ingestion of 6- FT (30 and 100 mg/kg) and pCPA (1 and 100 mg/kg) abolished the increase in plasma tryptophan during the day, and total plasma tryptophan concentrations were reduced compared with control levels at the same time of the day. The duration of each effect appeared to be related to the plasma half time of the inhibitor.

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Biological Half-Life
The plasma half times for 6-FT and pCPA were about 3.5 and 10.5 hours.

Interactions
This study examined the effects of serotonergic depletion and beta-adrenergic antagonism on performance in both visible platform and hidden platform versions of the water maze task. Male Long-Evans rats received systemic injections of p-chlorophenylalanine (500 mg/kg x 2) to deplete serotonin, or propranolol (20 or 40 mg/kg) to antagonize beta-adrenergic receptors. Some rats received treatments in combination. To separate strategies learning from spatial learning, half of the rats underwent Morris' water maze strategies pretraining before drug administration and spatial training. Individual depletion of serotonin or antagonism of beta-adrenergic receptors caused few or no impairments in either naive or pretrained rats in either version of the task. In contrast, combined depletion of serotonin and antagonism of beta-adrenergic receptors impaired naive rats in the visible platform task and impaired both naive and strategies-pretrained rats in the hidden platform task, and also caused sensorimotor impairments. ...
The goal of this study was to assess the interactive effects of chronic anabolic androgenic steroid (AAS) exposure and brain serotonin (5-hydroxytryptamine, 5-HT) depletion on behavior of pubertal male rats. Serotonin was depleted beginning on postnatal day 26 with parachlorophenylalanine (PCPA 100 mg/kg, every other day); controls received saline. At puberty (P40), half the PCPA-treated rats and half the saline-treated rats began treatment with testosterone (T, 5 mg/kg, 5 days/week). Behavioral measures included locomotion, irritability, copulation, partner preference, and aggression. Animals were tested for aggression in their home cage, both with and without physical provocation (mild tail pinch). Brain levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were determined using HPLC. PCPA significantly and substantially depleted 5-HT and 5-HIAA in all brain regions examined. Chronic T treatment significantly decreased 5-HT and 5-HIAA in certain brain areas, but to a much lesser extent than PCPA. Chronic exposure to PCPA alone significantly decreased locomotor activity and increased irritability but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on locomotion, irritability, or sexual behavior but increased partner preference and aggression. The most striking effect of combining T+PCPA was a significant increase in attack frequency as well as a significant decrease in the latency to attack, particularly following physical provocation. Based on these data, it can be speculated that pubertal AAS users with low central 5-HT may be especially prone to exhibit aggressive behavior.
...The dose-dependency and time-course of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy")-nduced perturbations of cerebral glucose metabolism in freely moving rats /was investigated/ ... A single dose of MDMA (2-10-20 mg/kg iv) evoked a transient increase of interstitial glucose concentrations in striatum (139-223%) with rapid onset and of less than 2 hr duration, a concomitant but more prolonged lactate increase (>187%) at the highest MDMA dose and no significant depletions of striatal serotonin. Blood glucose and lactate levels were also transiently elevated (163 and 135%) at the highest MDMA doses. The blood glucose rises were significantly related to brain glucose and brain lactate changes. The metabolic perturbations in striatum and the hyperthermic response (+1.1 degrees C) following systemic MDMA treatment were entirely blocked in p-chlorophenylalanine pre-treated rats, indicating that these effects are mediated by endogenous serotonin.
This study examined the effect of both separate and combined depletion of brain somatostatin and serotonin on acquisition of the water maze (WM) task. Naive male Long-Evans rats received injections of p-chlorophenylalanine (PCPA; 500 mg/kg x 2) to deplete serotonin or cysteamine (90 or 200 mg/kg) to deplete somatostatin, or both treatments prior to spatial and reversal training in the water maze. Some rats first received Morris' nonspatial pretraining to train them in the behavioral strategies that are required for successful spatial place learning in this task, prior to drug treatment and spatial training. A detailed behavioral analysis indicated that somatostatin or serotonin depletion alone caused little or no impairment in naive animals. Depletion of both somatostatin and serotonin in naive rats impaired performance, with differences in the impairments that depended on the dose of cysteamine. Nonspatially pretrained rats were not impaired. Thus, neither somatostatin nor serotonin alone is crucial for the water maze task, but impairments occur if both somatostatin and serotonin are depleted in naive rats. The results indicate that some of the performance impairment was due to strategies impairment rather than a spatial place learning impairment. Depletion of both somatostatin and serotonin in naive rats produces results comparable to the spatial navigation deficits seen in some Alzheimer patients and suggests that combinations of antagonist treatments may better model this disorder than single antagonist treatments do.
For more Interactions (Complete) data for Fenclonine (11 total), please visit the HSDB record page.

[1]. M Jouvet. Sleep and serotonin: an unfinished story. Neuropsychopharmacology. 1999 Aug;21(2 Suppl):24S-27S.

[2]. Prostaglandins: antinociceptive effect of prostaglandin E1 in the rat. Clin Exp Pharmacol Physiol. 1977 May-Jun;4(3):247-55.

[3]. Paracetamol potentiates the antidepressant-like and anticompulsive-like effects of fluoxetine. Behav Pharmacol. 2015 Apr;26(3):268-81.

[4]. In silico Analysis and Experimental Validation of Lignan Extracts from Kadsura longipedunculata for Potential 5-HT1AR Agonists. PLoS One . 2015 Jun 15;10(6):e0130055.

2-amino-3-(4-chlorophenyl)propanoic acid is a phenylalanine derivative.
A selective and irreversible inhibitor of tryptophan hydroxylase, a rate-limiting enzyme in the biosynthesis of serotonin (5-HYDROXYTRYPTAMINE). Fenclonine acts pharmacologically to deplete endogenous levels of serotonin.

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Mechanism of Action
Administration of the specific serotonin depletor p-chlorophenylalanine to rats resulted in marked inhibition of tryptophan hydroxylase of the brain. The enzyme inhibition can be correlated with and is assumed to be responsible for brain serotonin depletion. Although p-chlorophenylalanine is a competitive inhibitor of tryptophan hydroxylase in vitro, it causes an irreversible inactivation of the enzyme in vivo. The findings also support the conclusion that tryptophan hydroxylation is the rate-limiting step in serotonin biosynthesis.

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Therapeutic Uses
Enzyme Inhibitors; Serotonin Antagonists
The clinical and biochemical features of a patient with flushing and severe diarrhea due to the carcinoid syndrome are described. The patient had a paradoxical response to the tryptophan hydroxylase inhibitor parachlorophenylalanine with complete abolition of flushing and no effect on the diarrhea. Treatment with this drug was limited by adverse effects. /Former/

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Drug Warnings
... When the 5-HT concentration in sexually deficient men is sufficiently decreased with parachlorophenylalanine (PCPA) treatment and testosterone levels increased following its administration, a vivid sexual stimulation appears in about half of the untractable cases. Similar results are observed by substituting testosterone with monoamine oxydase inhibitor (MAOI) in PCPA-treated volunteers. . ...
A case is reported of a patient with carcinoid syndrome who developed a exogenous psychosis while under treatment with the serotonin-inhibitor p-chlorophenylalanine (PCPA). Partial symptoms similar to delirium and schizophrenia were exhibited.

C9H10CLNO2

199.6342

199.04

C, 54.15; H, 5.05; Cl, 17.76; N, 7.02; O, 16.03

7424-00-2

51274-82-9 (hydrochloride); 23633-07-0 (HCl); 7424-00-2

4652

White to off-white solid powder

1.3±0.1 g/cm3

339.5±32.0 °C at 760 mmHg

>240 °C (dec.)(lit.)

159.1±25.1 °C

0.0±0.8 mmHg at 25°C

1.590

1.71

63.32

2

3

3

13

179

0

NIGWMJHCCYYCSF-UHFFFAOYSA-N

InChI=1S/C9H10ClNO2/c10-7-3-1-6(2-4-7)5-8(11)9(12)13/h1-4,8H,5,11H2,(H,12,13)

Alanine, 3-(4-chlorophenyl)-, DL-

4-Chloro-DL-phenylalanine; PCPA; CP-10188; CP-10,188; CP10,188; CP 10,188; CP-10188; CP10188; CP 10188; Fenclonine; DL-3-(4-Chlorophenyl)alanine; Fenclonin; NSC 77370; p-Clorophenylalanine.

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 (~500.93 mM)
H2O : ~4.55 mg/mL (~22.79 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (12.52 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: ≥ 2.5 mg/mL (12.52 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 25.0 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: ≥ 2.5 mg/mL (12.52 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 25.0 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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配方 4 中的溶解度: 20 mg/mL (100.19 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*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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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。