Tryptophan hydroxylase

Establishment of Fenclonine/PCPA-induced insomnia rat model [4]
Male SD rats (12 rats per group) were assigned to one of six groups. Three groups received oral KL (4 g/kg, 8 g/kg, 12 g/kg) continuously for 7 days, followed by i.p.  Fenclonine/PCPA (300 mg/kg) at day 4 for three days. Two groups received oral saline (control group) and buspirone (positive group), followed by i.p.  Fenclonine/PCPA (300 mg/kg) at day 4 for three days. Saline was given to one group as a blank group. The dose of KL was converted to the quality of the original plants. The preparing training for the FST and TST were undertaken on day 3 after treatment. Finally, the FST and TST immobile times were measured on day 6. After 7 days of treatment, the rats were anesthetized and sacrificed by cervical dislocation, and the brains were removed and placed immediately on ice.
Pathogenic principle [4]
Fenclonine can inhibit the synthesis of serotonin (5-HT), induce 5-HT depletion, and lead to insomnia.

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Treatment with  Fenclonine/PCPA (ip; 100 mg/kg; once daily; 3 d) inhibits the antinociceptive activity induced by morphine [2]. Paracetamol at a dose of 50 mg/kg was completely eliminated after pretreatment with fenclonine (ip; 300 mg/kg; once daily; 3 days).

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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.52 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.52 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 25.0 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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (12.52 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 20 mg/mL (100.19 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)