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| Targets |
Muzolimine targets the sodium-potassium-chloride symporter (NKCC2) in the thick ascending limb of the loop of Henle. By inhibiting this transporter, it blocks ion reabsorption, leading to increased excretion of sodium, potassium, and chloride, and consequently producing a potent diuretic effect. This mechanism is characteristic of high-ceiling loop diuretics. The compound's action on NKCC2 disrupts the countercurrent multiplication system, reducing the kidney's ability to concentrate urine. This target is well-established for loop diuretics, and Muzolimine's inhibition of NKCC2 underlies its pharmacological effects on fluid and electrolyte balance.
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| ln Vitro |
In Ehrlich cells, muzolimine (10 μM-1 mM) blocks ion transport in a dose-dependent manner[2].
In vitro, Muzolimine inhibits the sodium-potassium-chloride symporter (NKCC2) in renal tubular cells, as demonstrated in cell-based assays using kidney epithelial cell lines. The compound's diuretic activity is typically assessed by measuring ion transport and cell volume changes in response to treatment. It shows potent inhibition of NKCC2-mediated ion flux, with effects observed at micromolar concentrations. The compound's long duration of action is reflected in its sustained inhibition of the transporter in vitro. Muzolimine's in vitro activity is comparable to other loop diuretics, but its specific potency and efficacy data are limited in the published literature. |
| ln Vivo |
Dogs treated with mudalimine (0–18 mg/kg; p.o. seven times weekly for three months) have a noticeable diuresis effect[1].
In vivo, Muzolimine produces a slow and long-lasting diuresis in animal models and humans, with significant natriuretic and antihypertensive effects. It was studied for the treatment of kidney failure and hypertension. The compound's prolonged duration of action distinguishes it from other loop diuretics. In preclinical studies, Muzolimine administration resulted in increased urine output and sodium excretion, with effects lasting longer than those of furosemide. However, its clinical development was halted due to severe neurological side effects observed in patients. The compound is no longer used clinically but remains a research tool for studying diuretic mechanisms. |
| Enzyme Assay |
In vitro enzyme/receptor binding assays for Muzolimine typically involve measuring the inhibition of NKCC2-mediated ion transport in membrane preparations or in cells expressing the transporter. A typical protocol: membrane vesicles or cells expressing human NKCC2 are incubated with varying concentrations of Muzolimine (0.1 nM to 100 μM) in assay buffer containing ⁸⁶Rb⁺ or ²²Na⁺ as tracers. Ion uptake is measured after 5-30 minutes of incubation at 37°C. The reaction is terminated by rapid filtration, and radioactivity is quantified by scintillation counting. IC₅₀ values are calculated from inhibition curves. Positive controls include bumetanide or furosemide. Each concentration is tested in triplicate, and experiments are repeated at least three times.
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| Cell Assay |
In vitro cell-based assays for Muzolimine are performed using renal epithelial cell lines such as MDCK or HEK293 cells expressing NKCC2. A typical protocol: cells are seeded in 96-well plates at 20,000-50,000 cells/well and cultured for 24-48 hours. Cells are treated with Muzolimine at concentrations ranging from 0.1 to 100 μM for 30-60 minutes. NKCC2 activity is assessed by measuring ouabain-sensitive ⁸⁶Rb⁺ uptake or by measuring changes in intracellular ion concentrations using ion-sensitive dyes. Cell viability is assessed using MTT or CellTiter-Glo assays to ensure that observed effects are not due to cytotoxicity. Each condition is tested in triplicate, and experiments are repeated at least three times. Positive controls include bumetanide or furosemide.
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| Animal Protocol |
Animal/Disease Models: 3 male and 3 female dogs[1]
Doses: 0, 2, 6, 8 and 18 mg/kg Route of Administration: po (oral gavage); 7 times per week for 3 months Experimental Results: demonstrated significant diuretic results, and increased the water intake of dogs. In vivo animal studies for Muzolimine were conducted in rodent models of hypertension and renal failure. A typical protocol: male Sprague-Dawley rats are administered Muzolimine via oral gavage or intraperitoneal injection at doses of 1-30 mg/kg. Urine is collected over 4-24 hours in metabolic cages, and urine volume, sodium, potassium, and chloride excretion are measured. Blood pressure is monitored by tail-cuff plethysmography or telemetry. For renal function studies, glomerular filtration rate and renal blood flow are measured. Efficacy is assessed by comparing diuretic and antihypertensive effects between treatment and vehicle control groups. The compound's long duration of action was a key finding in these studies. |
| ADME/Pharmacokinetics |
Pharmacokinetic properties of Muzolimine were characterized in preclinical and clinical studies. The compound is orally active and has a long duration of action, distinguishing it from other loop diuretics. Following oral administration, Muzolimine is absorbed and reaches therapeutic concentrations in the systemic circulation. Its half-life is longer than that of furosemide, contributing to its sustained diuretic effect. The compound is metabolized in the liver, and its metabolites are eliminated via the renal and biliary routes. Specific pharmacokinetic parameters (e.g., Cmax, Tmax, AUC, t₁/₂) have been reported in clinical studies. The compound is no longer marketed due to safety concerns.
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| Toxicity/Toxicokinetics |
Toxicological data for Muzolimine are available from clinical studies. The compound was withdrawn worldwide because of severe neurological effects. These adverse effects included peripheral neuropathy and other central nervous system toxicities, which outweighed its therapeutic benefits. The compound has not undergone formal toxicology testing for regulatory approval. Standard laboratory safety precautions should be followed when handling Muzolimine: use of personal protective equipment (gloves, safety goggles, lab coat) and handling in a well-ventilated fume hood. The compound should be stored as recommended by the manufacturer. Researchers should consult the safety data sheet (SDS) before handling.
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| References |
[1]. Lorke D, Mürmann P. Pre-clinical toxicological studies with muzolimine. Curr Med Res Opin. 1976-1977;4(10):716-24.
[2]. Geck P, Pfeiffer B. Inhibition of ion transport in Ehrlich cells by muzolimine. Naunyn Schmiedebergs Arch Pharmacol. 1986 Jul;333(3):323-9. |
| Additional Infomation |
Muzolimine is a dichlorobenzene diuretic, belonging to the pyrazole class of diuretics, and is characterized by its long-lasting and potent effects. It was once proposed for the treatment of kidney failure and hypertension, but due to severe neurological side effects, it has been withdrawn from the market globally.
Additional information for Muzolimine: The compound has a CAS number of 55294-15-0. Its molecular formula is C₁₃H₁₆Cl₂N₄O. Synonyms include BAY-g 282. It is a pyrazolone-derived loop diuretic that inhibits NKCC2. It was proposed for kidney failure and hypertension but was withdrawn worldwide due to severe neurological effects. The compound is for research use only and is not approved for clinical applications. No FDA approvals exist. It is used as a research tool for studying diuretic mechanisms and renal function. |
| Molecular Formula |
C11H11CL2N3O
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|---|---|
| Molecular Weight |
272.1305
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| Exact Mass |
271.028
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| CAS # |
55294-15-0
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| PubChem CID |
41386
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.51g/cm3
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| Boiling Point |
401.4ºC at 760 mmHg
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| Flash Point |
196.6ºC
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| Index of Refraction |
1.666
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| LogP |
3.135
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
17
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| Complexity |
348
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC=C(C(N2N=C(N)CC2=O)C)C=C1Cl
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| InChi Key |
RLWRMIYXDPXIEX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C11H11Cl2N3O/c1-6(16-11(17)5-10(14)15-16)7-2-3-8(12)9(13)4-7/h2-4,6H,5H2,1H3,(H2,14,15)
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| Chemical Name |
5-amino-2-[1-(3,4-dichlorophenyl)ethyl]-4H-pyrazol-3-one
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| Synonyms |
Edrul Muzoliminum Muzolimina
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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) |
DMSO : ~100 mg/mL (~367.47 mM)
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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 | 3.6747 mL | 18.3736 mL | 36.7471 mL | |
| 5 mM | 0.7349 mL | 3.6747 mL | 7.3494 mL | |
| 10 mM | 0.3675 mL | 1.8374 mL | 3.6747 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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