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| Targets |
D3 Receptor; PNU-177864 primarily targets the dopamine D3 receptor (D3R), where it functions as an antagonist. D3 receptors are predominantly located in the limbic regions of the brain and are involved in cognition, emotion, and reward pathways, making them a classic target for schizophrenia therapy.
PNU-177864 HCl targets the dopamine D3 receptor (D3R), a G protein-coupled receptor that is predominantly expressed in the limbic system and is involved in reward, motivation, and cognition. It is a selective antagonist with high affinity for D3R. By blocking D3R signaling, the compound modulates reward pathways and motivational circuits. Its selectivity for D3R makes it a valuable tool for studying addiction, compulsive behaviors, and neuropsychiatric disease mechanisms. |
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| ln Vitro |
In radioligand binding assays, PNU-177864 demonstrates high affinity for the human dopamine D3 receptor with an inhibition constant (Ki) of 38.2 nM. These assays are typically performed using CHO cell lines overexpressing the human D3 receptor and the radioligand [3H]-7-OH-DPAT.
PNU-177864 HCl exhibits potent in vitro activity as a D3 receptor antagonist. Its activity is assessed in receptor binding assays measuring its affinity for D3, D2, and other dopamine receptors. Functional assays measuring dopamine-induced signaling (e.g., cAMP accumulation, ERK phosphorylation) are used to confirm antagonist activity. Its selectivity for D3 over other dopamine receptors is a key feature. |
| ln Vivo |
The medication PNU-177864 (12.5-200 mg/kg; oral gavage; daily; 2-4 weeks; Sprague-Dawley rats) causes phospholipidosis in atypical target organs in dogs or rats, such as the pituitary, hair follicles, and epididymis[1].
PNU-177864 exhibited antipsychotic-like activity in animal models. However, its in vivo activity was overshadowed by significant toxicity. It induced systemic phospholipidosis in rats and dogs following oral administration, specifically causing myofiber degeneration and necrosis in rat skeletal muscle, leading to severe myopathy. In vivo, PNU-177864 HCl induces phospholipid metabolism and exhibits antischizophrenia activity. In Sprague-Dawley rats, the medication (12.5-200 mg/kg; oral gavage; daily; 2-4 weeks) causes phospholipidosis in atypical target organs such as the pituitary, hair follicles, and epididymis. Its ability to modulate reward pathways makes it a valuable model for studying addiction and neuropsychiatric disorders. |
| Enzyme Assay |
Membrane Preparation: Harvest CHO cells overexpressing human D3 receptors, lyse cells, and extract membrane fractions via centrifugation.
Incubation: Incubate membranes with radioligand [3H]-7-OH-DPAT (Kd 1.4 nM) and various concentrations of PNU-177864 in assay buffer at room temperature. Define Non-specific Binding: Use a high concentration of haloperidol to define non-specific binding. Harvest & Count: Terminate the reaction by rapid vacuum filtration through GF/B filters. Wash filters, dry them, and measure bound radioactivity using a liquid scintillation counter. Analysis: Plot competitive binding curves and calculate the Ki value (38.2 nM) for PNU-177864. In vitro receptor binding assays for PNU-177864 HCl involve measuring its affinity for dopamine D3, D2, and other receptors. These assays use membrane preparations from cells expressing recombinant receptors and radiolabeled ligands. The compound is incubated with the receptor and the radioligand, and the displacement is measured to calculate the Ki values. Functional assays measuring cAMP accumulation or GTPγS binding are used to confirm antagonist activity. |
| Cell Assay |
Seeding: Seed CHO cells stably expressing human D3 receptors into 96-well plates and culture until appropriate confluence.
Treatment: Remove medium and add assay buffer containing various concentrations of PNU-177864 and a standard agonist (e.g., dopamine). Signal Detection: As D3 is a Gi-coupled GPCR, antagonist activity is measured via cAMP levels. Add Forskolin to stimulate cAMP production. If PNU-177864 blocks the receptor, it reverses the agonist-induced inhibition of cAMP, leading to increased cAMP levels. Readout: Detect intracellular cAMP concentration using HTRF or ELISA. Analysis: Calculate the IC50 of PNU-177864 to confirm its antagonistic function. In vitro cellular assays for PNU-177864 HCl are conducted in cells expressing dopamine D3 receptors. Cells are treated with the compound at various concentrations, and dopamine-induced signaling (e.g., cAMP accumulation) is measured. Cell viability and proliferation are assessed using standard assays. The compound's effects on neuronal function can be studied in primary neuronal cultures. |
| Animal Protocol |
Animal/Disease Models: Male and female SD (Sprague-Dawley) rats (8-9weeks old)[1]
Doses: 12.5 mg/kg, 50 mg/kg (for 2 weeks), or 200 mg/kg; 8 mg/kg, 25 mg/kg, or 80 mg/kg (for 4 weeks) Route of Administration: po (oral gavage); daily; for 2-4 weeks Experimental Results: Induced phospholipidosis in unusual target organs in dogs or rats including epididymis, pituitary, and hair follicles. Animal Selection & Grouping: Use SD rats or Beagle dogs in repeat-dose toxicity studies. Establish control groups and PNU-177864 treatment groups (Rats: ≥ 80 mg/kg/day; Dogs: ≥ 32 mg/kg/day). Administration: Administer once daily via oral gavage for several weeks (e.g., 28 or 90 days). Observation: Monitor general status, behavior, and mortality daily. Record body weight and food intake periodically. Toxicokinetics: Collect blood at specific time points to measure plasma drug concentrations. Necropsy & Pathology: Euthanize animals at study termination. Perform gross necropsy, weigh major organs, and collect tissues (epididymis, skeletal muscle, liver, lung) for histopathological examination (light and electron microscopy) to assess phospholipidosis and necrosis. In vivo animal experiments with PNU-177864 HCl are conducted in rodent models of neuropsychiatric disorders. The compound is administered orally or by injection at various doses (e.g., 12.5-200 mg/kg). Behavioral assays (e.g., locomotor activity, reward-related behaviors), biochemical measurements (e.g., phospholipid levels), and histopathological analysis are performed. These studies evaluate the compound's efficacy and its effects on phospholipid metabolism. |
| ADME/Pharmacokinetics |
PNU-177864 is orally active, indicating good oral absorption. Specific parameters like half-life or bioavailability are not detailed in the available summaries, but the drug exposure levels in rats and dogs were sufficient to induce significant toxicity.
PNU-177864 HCl is an orally active compound. It has a molecular formula of C18H21F3N2O3S·HCl and a molecular weight of approximately 439 g/mol. The compound is soluble in DMSO and is typically stored at -20°C. Its half-life and bioavailability have been characterized in preclinical studies. It induces phospholipidosis in target organs. |
| Toxicity/Toxicokinetics |
The principal toxicity of PNU-177864 is cationic amphiphilic drug-induced phospholipidosis. While epididymal epithelial cell phospholipidosis was prominent without degeneration in rats and dogs, the critical adverse effect was multifocal myofiber degeneration and necrosis in rat skeletal muscle (myopathy), leading to developmental termination. Other affected sites included lymphoid tissues, lungs, adrenal glands, and liver. Notably, phospholipidosis was reversible (except in the epididymis) after a 6-week recovery period.
PNU-177864 HCl has been evaluated for safety in preclinical studies. The compound induces phospholipidosis in rats, which is a potential safety concern. The compound is intended for research use only and is not approved for human therapeutic use. Standard laboratory safety precautions should be followed when handling this compound. |
| References |
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| Additional Infomation |
PNU-177864 HCl is a potent, selective, and orally active dopamine D3 receptor antagonist. It has antischizophrenia activity and induces phospholipid metabolism in vivo. It was developed by Pfizer for neuropsychiatric disorders and is used to study addiction, compulsive behaviors, and neuropsychiatric disease mechanisms. It causes phospholipidosis in atypical target organs in rats.
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| Molecular Formula |
C18H22CLF3N2O3S
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| Molecular Weight |
438.89209318161
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| Exact Mass |
438.099
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| CAS # |
1783978-03-9
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| Related CAS # |
PNU-177864;250266-51-4
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| PubChem CID |
56972219
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
28
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| Complexity |
521
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.S(C1C=CC(=CC=1)OC(F)(F)F)(NC1C=CC(=CC=1)CCNCCC)(=O)=O
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| InChi Key |
UOMDLHQTLPWCCE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H21F3N2O3S.ClH/c1-2-12-22-13-11-14-3-5-15(6-4-14)23-27(24,25)17-9-7-16(8-10-17)26-18(19,20)21;/h3-10,22-23H,2,11-13H2,1H3;1H
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| Chemical Name |
N-[4-[2-(propylamino)ethyl]phenyl]-4-(trifluoromethoxy)benzenesulfonamide;hydrochloride
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| Synonyms |
PNU177864 HCl PNU 177864 HCl
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2785 mL | 11.3924 mL | 22.7848 mL | |
| 5 mM | 0.4557 mL | 2.2785 mL | 4.5570 mL | |
| 10 mM | 0.2278 mL | 1.1392 mL | 2.2785 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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