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| Targets |
SSRI; tricyclic antidepressant (TCA)
Pipofezine HCl primarily targets the serotonin transporter (SERT), acting as a serotonin reuptake inhibitor. It also exhibits antihistamine activity, contributing to its sedative effects. As a tricyclic antidepressant, it may also interact with other neurotransmitter receptors including adrenergic and cholinergic receptors, though its affinity for these targets is less clearly defined. Its mechanism involves increasing synaptic serotonin levels by blocking its reuptake into presynaptic neurons. |
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| ln Vitro |
Pipofezine has sedative, antihistamine, anticholinergic and antiadrenergic activity in addition to its antidepressant action.
Pipofezine Dihydrochloride Monohydrate 2 [5] The MicroED structure 2 was solved in a monoclinic P 21/c space group at the resolution of 0.82 Å (Figure 2b and Figure 3), with the unit cell parameters of a = 6.88 Å, b = 15.61 Å, c = 15.93 Å, α = 90.0°, β = 97.2°, γ = 90.0°. Two conforms, namely 2a and 2b were identified in the uniFig t cell. Each can be transformed by inversion symmetry or 180° rotation of C11‒N4/C11′‒N4′ bond. The crystal packing is formed mainly by hydrogen bonds and ion-dipole interactions between 2a/2b and chloride anions along b- and c-axes, i.e. hydrogen bonds N5/N5′─H···Cl1 (3.01 Å) and N3/N3′─H···O2 (2.67 Å); ion-dipole interactions between CH atoms and chloride anions (Figure S3, Supporting Information). The water molecules serve as hydrogen bond donors to Cl1 or Cl2 anions that bridge 2a and 2b molecules together (Figure S3, Supporting Information). The packing along the a-axis is facilitated by strong parallel-displaced pi-stacking interactions between the phenyl and pyridazine rings in 2a and 2b (3.65 Å). In 2, bond angles are mostly fixed, with only one freely rotating bond (C10‒C11‒N4‒C15 and C10′‒C11′‒N4′‒C15′, measured at ±178.60° in 2a and 2b), generating a co-planar arrangement of piperazine ring and tricyclic moiety (Figure S4, Supporting Information).[5] Pipofezine HCl's in vitro activity is characterized by its potent inhibition of serotonin reuptake. It demonstrates antidepressant activity in various in vitro models of serotonergic neurotransmission. The compound's sedative effects suggest additional antihistamine activity. Its IC50 value for serotonin reuptake inhibition and selectivity profile are key parameters for characterizing its activity. However, detailed quantitative in vitro data are limited in publicly available sources. |
| ln Vivo |
Pipofezine HCl demonstrates in vivo antidepressant activity in animal models of depression. As a clinically approved drug in Russia, its efficacy has been established in human patients with depression. It exhibits sedative effects in vivo, consistent with its antihistamine activity. The compound's therapeutic effects are attributed to increased serotonergic neurotransmission. Its in vivo pharmacokinetics and pharmacodynamics have been characterized through clinical use.
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| Enzyme Assay |
2‒hSERT Complexes[5]
2 was tested at the central (S1) and allosteric (S2) sites in hSERT (Figure S12c, Supporting Information),[32] however the final docking center was found near S2 site due to the weak binding observed in S1 site (i.e., only the hydrophobic interactions). A salt bridge between Asp98 and piperazine ring, together with one pi-stacking (Phe335), one pi-cation interaction (Arg104), and three hydrophobic interactions (Phe335, Phe556) to the tricyclic moiety stabilized the binding complex of 2/hERT (Figure 4c). The structures of 2 in its drug-formulation state and biologically active state are very similar, with only 3–6° rotation C11′‒N4′ bond (Figure S4, Supporting Information), and maintain the piperazine ring and tricyclic moiety in a nearly co-planar geometry (C10‒C11‒N4‒C15≈180°) for both states. The minimum conformational changes ensure small entropy differences upon binding which is beneficial for the binding of 2 to the receptor. Serotonin reuptake inhibition assays are performed using synaptosomal preparations or cells expressing the serotonin transporter. [3H]-Serotonin uptake is measured in the presence of varying concentrations of Pipofezine HCl. The reaction is incubated at 37°C for a specified period, and uptake is terminated by rapid filtration. Radioactivity retained on filters is quantified by scintillation counting. IC50 values for inhibition of serotonin uptake are determined by non-linear regression analysis. Each concentration is tested in duplicate with appropriate positive controls (e.g., fluoxetine) and vehicle controls. |
| Cell Assay |
Cellular activity of Pipofezine HCl is evaluated in neuronal cell lines or primary neuronal cultures expressing serotonin transporters. Cells are cultured in appropriate media at 37°C with 5% CO2 and treated with varying concentrations of the compound. Serotonin uptake is measured using [3H]-serotonin or fluorescent serotonin analogs. Intracellular serotonin levels can be quantified by HPLC or ELISA. Cell viability is assessed using MTT or LDH assays to ensure compound concentrations are non-cytotoxic. Each experiment includes known serotonin reuptake inhibitors as positive controls and vehicle controls.
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| Animal Protocol |
In vivo studies of Pipofezine HCl were conducted in animal models of depression prior to its clinical approval. Standard behavioral tests include the forced swim test, tail suspension test, and learned helplessness models in rodents. The compound is administered orally or intraperitoneally at various doses. Antidepressant-like effects are assessed by reduced immobility time. Sedative effects are evaluated in open field or locomotor activity tests. Sample sizes typically range from 8-12 animals per group. Clinical efficacy has been established in human trials in Russia.
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| ADME/Pharmacokinetics |
Pipofezine HCl has a molecular weight of 333.82 g/mol and a molecular formula of C16H20ClN5O. Solubility: soluble in DMSO, not in water. Storage: dry, dark, 0-4°C for short term, -20°C for long term. Appearance: solid powder. Purity: >98%. As a TCA, it is metabolized in the liver and excreted renally. Its half-life and bioavailability have been characterized through clinical use. It is orally active and approved for human use in Russia.
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| Toxicity/Toxicokinetics |
Pipofezine HCl has been clinically evaluated and is approved in Russia for the treatment of depression. Common adverse effects may include sedation, anticholinergic effects (dry mouth, constipation), and antihistamine-related drowsiness. It is generally well-tolerated at therapeutic doses. Standard toxicology studies have demonstrated an acceptable safety profile in preclinical models. As with other TCAs, overdose can be serious and requires medical attention. It is contraindicated in patients with certain cardiovascular conditions.
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| References |
[1]. Azaphen: a return to clinical practice.Zh Nevrol Psikhiatr Im S S Korsakova. 2005;105(10):55-6.
[2]. Azaphen in the treatment of enuresis in children.Psychiatr Pol. 1977 Jan-Feb;11(1):29-33. [3]. A comparison of the effect of the tricyclic antidepressants azaphen and imizin on the gastrointestinal tracts of experimental animals.Farmakol Toksikol. 1975 Jan-Feb;38(1):29-32. [4]. Proceedings: Influence of azaphen, a new antidepressive drug, on the human EEG. Act Nerv Super (Praha). 1974;16(4):245-6. [5]. Uncovering the Elusive Structures and Mechanisms of Prevalent Antidepressants. Advanced Therapeutics 2024, 2400117. https://onlinelibrary.wiley.com/doi/full/10.1002/adtp.202400117 |
| Additional Infomation |
Most treatments for major depressive disorder work by inhibiting monoamine transporters (which are essential for the reuptake of monoamine neurotransmitters) or monoamine oxidases (which are essential for the degradation of monoamine neurotransmitters). Analyzing the experimental three-dimensional structures of these antidepressants in their pharmaceutical formulations is crucial for precise drug design and development. This study is the first to use microcrystalline electron diffraction (MicroED) to directly resolve the atomic-level three-dimensional structures of five of the most commonly used antidepressants (reboxetine, piperazine, amisulfosine, phenelzine, and bifemyllan) from commercially available active ingredient powders. Their binding modes were studied by molecular docking, revealing key interactions and conformational changes in the biologically active state. This study highlights the importance of combining MicroED and molecular docking in revealing elusive drug structures and mechanisms, which can contribute to further drug development. [5]
Pipofezine HCl is also known as Azafen, Azaphen, and Pipofezine hydrochloride. Its IUPAC name is 5-methyl-3-(4-methylpiperazin-1-yl)pyridazino[3,4-b][1,4]benzoxazine hydrochloride. It is a tricyclic antidepressant approved in Russia for depression treatment, introduced in the late 1960s. It acts as a serotonin reuptake inhibitor with sedative effects suggesting antihistamine activity. The compound is for research and clinical use in approved jurisdictions. |
| Molecular Formula |
C16H20CLN5O
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| Molecular Weight |
333.82
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| Exact Mass |
369.112
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| Elemental Analysis |
C, 57.57; H, 6.04; Cl, 10.62; N, 20.98; O, 4.79
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| CAS # |
24853-80-3
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| Related CAS # |
Azaphen dihydrochloride monohydrate;63302-99-8
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| PubChem CID |
159976
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| Appearance |
Typically exists as solids at room temperature
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| Boiling Point |
536ºC at 760 mmHg
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| Flash Point |
278ºC
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| Vapour Pressure |
1.46E-11mmHg at 25°C
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| LogP |
3.773
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
24
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| Complexity |
387
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| Defined Atom Stereocenter Count |
0
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| SMILES |
[H]Cl.[H]Cl.CN1C2=CC=CC=C2OC3=C1C=C(N4CCN(C)CC4)N=N3
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| InChi Key |
ZZVWCKAYZSAUKR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H19N5O.2ClH/c1-19-7-9-21(10-8-19)15-11-13-16(18-17-15)22-14-6-4-3-5-12(14)20(13)2;;/h3-6,11H,7-10H2,1-2H3;2*1H
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| Chemical Name |
5-methyl-3-(4-methylpiperazin-1-yl)pyridazino[3,4-b][1,4]benzoxazine;dihydrochloride
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| Synonyms |
Azaphen; 24853-80-3; Azafen; Pipofezine HCl; Pipofezine hydrochloride; MFB4TD413U; Azaphen hydrochloride; 5-methyl-3-(4-methylpiperazin-1-yl)pyridazino[3,4-b][1,4]benzoxazine;dihydrochloride;
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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 | 2.9956 mL | 14.9781 mL | 29.9563 mL | |
| 5 mM | 0.5991 mL | 2.9956 mL | 5.9913 mL | |
| 10 mM | 0.2996 mL | 1.4978 mL | 2.9956 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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