Tryptophan hydroxylase
Fenclonine (PCPA; CP-10188) is described as a serotonin synthesis inhibitor.[4]

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).

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Fenclonine (PCPA; CP-10188) is used to induce a serotonin-depleting insomnia model in rats. Intraperitoneal (i.p.) injection of PCPA (300 mg/kg) for three consecutive days successfully induces insomnia-like symptoms, characterized by increased immobility time in behavioral tests and biochemical changes related to serotonin signaling.[4]

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.

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Fenclonine (PCPA; CP-10188) is administered intraperitoneally at a dose of 300 mg/kg once daily for three consecutive days to induce a serotonin-depleted insomnia model in Sprague-Dawley rats. The model is validated using behavioral tests (forced swimming test and tail suspension test) and biochemical assays (Western blot and immunofluorescence for 5-HT1AR pathway proteins).[4]

Absorption, Distribution and Excretion
Six monkeys (mean weight 5.3 kg) and five monkeys (mean weight 7.5 kg) fed a controlled diet were orally administered 6-fluorotryptophan (6-FT) and p-chlorophenylalanine (pCPA). Plasma amino acid concentrations were determined using an amino acid analyzer. In the 6-FT study, free tryptophan was determined using balanced dialysis. Dosing intervals were at least 3 weeks. Each administration was given at 9:00 AM by mixing the drug with almond sugar. After administration of 10, 30, and 100 mg/kg 6-FT, the mean peak plasma concentrations of 6-FT were 24, 58, and 145 nmol/mL, respectively, all occurring at 11:00 AM. After administration of pCPA (10 and 100 mg/kg), the mean peak plasma concentrations of pCPA were 59 and 343 nmol/mL, respectively, with peaks occurring at 11:00 AM and 1:00 PM, respectively. After administration of pCPA (1 mg/kg), plasma concentrations could not be determined. The plasma half-lives of 6-FT and pCPA were approximately 3.5 hours and 10.5 hours, respectively. In the control study, plasma tryptophan concentrations gradually increased during the day, peaking in the afternoon. Elevations in plasma concentrations at 13:00 and 17:00 were highly statistically significant (P<0.01). After oral administration of 6-FT (30 and 100 mg/kg) and pCPA (1 and 100 mg/kg), the gradual increase in plasma tryptophan concentrations during the day disappeared, and total plasma tryptophan concentrations were lower at the same time point compared to the control group. The duration of each effect appeared to be related to the plasma half-life of the inhibitor.
Biological Half-Life The plasma half-lives of 6-FT and pCPA were approximately 3.5 and 10.5 hours, respectively.

Interactions
This study investigated the effects of serotonin depletion and β-adrenergic antagonists on performance on visible and hidden platforms in a 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 β-adrenergic receptors. Some rats received combined treatment. To differentiate between strategy learning and spatial learning, half of the rats underwent Morris water maze strategy pre-training before drug administration and spatial training. In both versions of the water maze task, serotonin depletion or β-adrenergic receptor antagonism alone caused little or no impairment in either untrained or trained rats. Conversely, the combined effects of serotonin depletion and β-adrenergic receptor antagonists impaired performance in untrained rats on the visible platform task and in untrained and strategy-pre-trained rats on the hidden platform task, and also led to sensorimotor dysfunction. This study aimed to evaluate the interaction between long-term exposure to anabolic androgens (AAS) and serotonin (5-HT) depletion in the brain on the behavior of adolescent male rats. Starting on day 26 after birth, rats were treated with serotonin-depleted p-chlorophenylalanine (PCPA, 100 mg/kg, every other day); the control group received saline injections. At puberty (P40), half of the rats in the PCPA-treated group and half in the saline-treated group began treatment with testosterone (T, 5 mg/kg, 5 days a week). Behavioral parameters included motor ability, irritability, mating behavior, mate preference, and aggression. Aggression was tested in the animals' cages with and without physical provocation (mild tail pinching). High-performance liquid chromatography (HPLC) was used to determine the levels of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the brain. PCPA significantly and substantially reduced 5-HT and 5-HIAA levels in all brain regions examined. Long-term testosterone (T) treatment significantly reduced 5-HT and 5-HIAA levels in some brain regions, but to a much lesser extent than PCPA. Long-term exposure to PCPA alone significantly reduced motor activity and increased irritability, but had no effect on sexual behavior, partner preference, or aggression. T alone had no effect on motor ability, irritability, or sexual behavior, but increased partner preference and aggression. The most significant effect of the T+PCPA combination was a significant increase in the frequency of aggression and a significant shortening of the aggression latency, especially after physical provocation. Based on these data, it can be inferred that individuals who used anabolic steroids (AAS) during adolescence and had low central serotonin (5-HT) levels may be more prone to exhibiting aggressive behavior.
...This study investigated the dose-dependency and time progression of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy")-induced glucose metabolism disorder in the brain of freely moving rats...A single intravenous injection of MDMA (2-10-20 mg/kg) caused a transient increase in striatal interstitial glucose concentration (139-223%), with a rapid onset and duration of less than 2 hours; simultaneously, at the highest dose of MDMA, lactate levels also showed an accompanying but longer-lasting increase (>187%); striatal serotonin levels did not show a significant decrease. At the highest dose of MDMA, blood glucose and lactate levels also showed transient increases (163% and 135%, respectively). The increase in blood glucose was significantly correlated with changes in brain glucose and brain lactate. The striatal metabolic disorder and the hyperthermic response (+1.1°C) following systemic MDMA administration were completely blocked in rats pretreated with p-chlorophenylalanine, indicating that these effects are mediated by endogenous serotonin. This study investigated the effects of depletion of somatostatin and serotonin, alone or in combination, on the acquisition of a water maze (WM) task. Untrained male Long-Evans rats were administered p-chlorophenylalanine (PCPA; 500 mg/kg x 2) to deplete serotonin, or cysteine (90 or 200 mg/kg) to deplete somatostatin, or both, before spatial and reverse training in the water maze. Some rats underwent Morris non-spatial pre-training before drug treatment and spatial training to learn the spatial location learning strategies required for successful completion of the task. Detailed behavioral analysis showed that reducing somatostatin or serotonin levels alone had little or no effect on untrained animals. Simultaneous reduction of somatostatin and serotonin levels in untrained rats impaired their behavioral performance, with the degree of impairment depending on the dose of cysteine. No behavioral impairment was observed in rats without spatial pre-training. Therefore, reducing somatostatin or serotonin levels alone is not crucial for the water maze task, but simultaneously reducing somatostatin and serotonin levels in untrained rats results in impaired behavioral performance. The results indicate that some of the behavioral impairment is due to strategy impairment rather than spatial location learning impairment. Simultaneous depletion of somatostatin and serotonin in untreated rats produces spatial navigation deficits similar to those observed in some Alzheimer's disease patients, suggesting that combined antagonist therapy may better mimic this disease than single antagonist therapy. For more complete data on interactions of fenclofen (11 in total), please visit the HSDB records 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)propionic acid is a derivative of phenylalanine. It is a selective and irreversible inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin (5-hydroxytryptamine) biosynthesis. Fenclonine's pharmacological action is to reduce endogenous serotonin levels. Mechanism of Action: Administration of the specific serotonin-depleting agent p-chlorophenylalanine to rats significantly reduced tryptophan hydroxylase activity in the brain. This enzyme inhibition is associated with and is considered a cause of serotonin depletion in the brain. Although p-chlorophenylalanine is a competitive inhibitor of tryptophan hydroxylase in vitro, it leads to irreversible inactivation of the enzyme in vivo. The results also support the conclusion that tryptophan hydroxylation is the rate-limiting step in serotonin biosynthesis. Therapeutic Uses: Enzyme inhibitor; Serotonin antagonist. This article describes the clinical and biochemical characteristics of a patient presenting with flushing and severe diarrhea due to carcinoid syndrome. This patient exhibited a paradoxical response to the tryptophan hydroxylase inhibitor p-chlorophenylalanine; the flushing symptoms completely disappeared, but the diarrhea symptoms did not improve. Treatment with this drug is limited due to adverse reactions. /Previous/

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Drug Warning>
…When treatment with p-chlorophenylalanine (PCPA) sufficiently reduces serotonin (5-HT) levels in men with low libido, and testosterone levels rise after administration, approximately half of the refractory cases experience intense sexual arousal. Similar results were observed in volunteers receiving PCPA treatment when testosterone was replaced with a monoamine oxidase inhibitor (MAOI). …
A case of carcinoid syndrome was reported in a patient who developed exogenous psychosis during treatment with the serotonin inhibitor p-chlorophenylalanine (PCPA). The patient presented with symptoms resembling delirium and parts of schizophrenia.

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Fenclonine (PCPA; CP-10188) was used as a pharmacological tool to deplete serotonin and establish a rat model of insomnia. This model was used to evaluate the sedative-hypnotic effects of extracts of Acanthopanax senticosus, which are believed to have 5-HT1AR agonist activity. [4]

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.)