Disobutamide
Disobutamide (SC-31828) is an orally active, blood-brain barrier permeable cationic amphiphilic ditertiary amine piperidine ring compound with antiarrhythmic properties. Disobutamide induces lysosomal phospholipid accumulation, which triggers extensive cytoplasmic vacuolization and leads to cell death. Disobutamide prolongs multiple electrocardiographic intervals in canine hearts, induces cardiac arrest at high doses, and causes decreased retinal reflectivity. Disobutamide can be used in studies related to arrhythmias, and also serves as a model drug for investigating the storage mechanisms and toxicity thresholds of intracellular amphiphilic compounds.
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- No. CAS: 68284-69-5
- Fòrmula: C23H38ClN3O
- Peso molecular:408.02
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Almacenamiento:
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Actividad biológica
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Chemical Information
- Protocolo
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Help & FAQs
Actividad biológica
Descripciòn
In Vitro
Disobutamide (1×10-4-10×10-4 M; 24 h) does not induce significant cytotoxicity (measured by LDH release) in rat urinary bladder carcinoma or rabbit aorta muscle cells at concentrations up to 10×10-4 M after 24 hours, but induces severe cytotoxicity in rat basophilic leukaemia cells at concentrations ≥4×10-4 M after 24 hours[1].
Disobutamide (10-3 M; 24 h) shows enhanced cellular uptake in rat urinary bladder carcinoma cells (RBT CC-8) with increased basicity of the culture medium, with clear cytoplasmic vacuoles forming at higher uptake levels[2].
Disobutamide (10-6-10-3 M; 30 min-6 hr) shows species-specific in vitro uptake by choroid plexus tissue, with highest uptake in rat choroid plexus, followed by monkey choroid plexus, then dog choroid plexus, and induces dose-dependent vacuolation in dog choroid plexus epithelial cells at concentrations ≥10-4 M[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
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Cell Line:rat urinary bladder carcinoma (RBT CC-8) cells, rabbit aorta muscle cells, rat basophilic leukaemia cells
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Concentration:1×10-4 M, 2×10-4 M, 4×10-4 M, 6×10-4 M, 8×10-4 M, 10×10-4 M
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Incubation Time:24 h
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Result:Caused LDH release relative to total enzyme of ≤5.2% at all tested concentrations in rat urinary bladder carcinoma cells.
Caused LDH release relative to total enzyme ranging from 5.3% at 1×10-4 M to 31.2% at 10×10-4 M in rabbit aorta muscle cells, a magnitude not indicative of cytotoxicity.
Caused LDH release relative to total enzyme of 2.2% at 1×10-4 M, 18.7% at 2×10-4 M, and 84.4-89.9% at 4×10-4 M to 10×10-4 M in rat basophilic leukaemia cells, indicating significant cytotoxicity at concentrations ≥4×10-4 M.
In Vivo
Disobutamide (10-300 mg/kg/day; p.o.; daily; 5 days-52 weeks) induces selective cytoplasmic vacuolation in Rattus norvegicus choroid plexus and epididymal epithelial cells at 300 mg/kg/day, causes lethal toxicity at the same dose with prolonged exposure, and induces hepatic phospholipidosis without cellular injury during long-term high-dose dosing[2].
Disobutamide (30-250 mg/kg; i.g.; daily; 4-35 days) induces dose-dependent lysosomal vacuolation (phospholipidosis) in multiple rat organs, with very severe choroid plexus epithelial vacuolation at 250 mg/kg, moderate changes at 100 mg/kg, and mild changes at 30 mg/kg, correlating[3].
Disobutamide (45 mg/kg; p.o.; daily; 35 days) induces vacuolation in multiple dog organs but not choroid plexus epithelium, while direct intraventricular administration (0.035 mg total dose; i.c.v.; single dose) causes choroid plexus epithelial vacuolation, linked to low drug penetration into CSF via oral dosing[3].
Disobutamide (90 mg/kg; i.g.; daily; 35 days) induces very severe choroid plexus epithelial vacuolation and dose-dependent vacuolation in other monkey organs, correlating with high choroid plexus drug concentration and increased CSF/serum ratio over time[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Jcl:SD rats (male and female, 5 weeks of age)[3]
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Dosage:30 mg/kg; 100 mg/kg; 250 mg/kg
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Administration:i.g.; daily; 13 weeks (30, 100, 250 mg/kg); i.g.; single dose (100, 250 mg/kg); i.g.; daily; 4, 7, or 35 days (100, 250 mg/kg)
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Result:Caused 10/16 males and 10/16 females to die of convulsions during weeks 1-9 at 250 mg/kg.
Reduced feed intake and depressed body weight gain in both sexes at 250 mg/kg.
Elevated total cholesterol in both sexes, phospholipid in males, and triglyceride in females at 250 mg/kg.
Decreased most organ weights in males, and thymus/spleen weights in females at 250 mg/kg.
Induced very severe vacuolation in choroid plexus epithelium, severe vacuolation in renal distal tubules and hepatocytes, moderate vacuolation in submaxillary gland, bronchus, uterine epithelium, cardiac muscle, coronary artery, and lung macrophages, slight vacuolation in stomach, small intestine, spleen macrophages, thymus macrophages, and bone marrow macrophages at 250 mg/kg.
Detected choroid plexus drug concentration of 11.8 mg/g, brain concentration of 26.2 μg/g, liver concentration of 604 μg/g, and kidney concentration of 403 μg/g after 35 days of 250 mg/kg dosing.
Caused muscle relaxation and prone position in females, slight feed intake decrease and body weight gain depression in males, slight thymus weight decrease in males, and slight vacuolation in submaxillary gland, bronchus, cardiac muscle, coronary artery, lung macrophages, thymus macrophages, and bone marrow macrophages at 100 mg/kg.
Induced large lysosome increase in choroid plexus epithelium after 4 days and vacuoles in large choroid plexus lysosomes after 7 days of 100 mg/kg dosing.
Caused slight thymus weight decrease in males and slight vacuolation in submaxillary gland, cardiac muscle, coronary artery, thymus macrophages, and bone marrow macrophages at 30 mg/kg.
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Animal Model:Beagle dogs (female, 13-17 months of age; male and female, 10 months of age)[3]
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Dosage:45 mg/kg; 0.035 mg total dose
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Administration:p.o.; daily; 35 days (45 mg/kg); i.c.v.; single dose (0.035 mg)
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Result:Induced severe vacuolation in stomach, small intestine, renal distal tubules, and bronchial epithelium, moderate vacuolation in spleen macrophages, slight vacuolation in esophagus, submaxillary gland, iris pigment epithelium, hepatocytes, cardiac muscle, coronary artery, aorta, intestinal muscle cells, lung macrophages, thymus macrophages, and bone marrow macrophages at 45 mg/kg p.o.
Detected choroid plexus drug concentration of 0.124 mg/g, brain concentration of 12.2 μg/g, liver concentration of 468 μg/g, and kidney concentration of 653 μg/g after 35 days of 45 mg/kg p.o. dosing.
Caused numerous enlarged lysosomes (some with vacuoles) in choroid plexus epithelial cells 3 hours after 0.035 mg i.c.v. dosing.
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Animal Model:Macaca fasciculata (female, adult age)[3]
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Dosage:90 mg/kg
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Administration:i.g.; daily; 35 days
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Result:Induced severe lymphocyte cytoplasmic vacuolation; one monkey showed elevated total cholesterol and phospholipid at 2 weeks.
Caused very severe vacuolation in choroid plexus epithelium, severe vacuolation in renal distal tubules and intestinal muscle cells, moderate vacuolation in stomach, small intestine, bronchial epithelium, uterine epithelium, hepatocytes, coronary artery, spleen macrophages, and bone marrow macrophages, slight vacuolation in esophagus, submaxillary gland, cardiac muscle, aorta, lung macrophages, and thymus macrophages.
Detected choroid plexus drug concentration of 30.233 mg/g, brain concentration of 18.7 μg/g, liver concentration of 1304 μg/g, and kidney concentration of 1092 μg/g after 35 days of dosing.
Showed higher CSF concentration at 24 hours and significantly higher CSF/serum ratio at 24 hours on day 35 compared to day 1.
Chemical Information
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No. CAS 68284-69-5
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Peso molecular 408.02
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Fòrmula C23H38ClN3O
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SMILES
O=C(C(CCN(C(C)C)C(C)C)(CCN1CCCCC1)C2=CC=CC=C2Cl)N
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Synonyms
SC-31828
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocolo
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
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Mammalian live/dead viability and cytotoxicity staining
Live/dead viability and cytotoxicity staining assays are based on the simultaneous detection of intracellular esterase activity in metabolically active (viable) cells and membrane integrity loss in non-viable cells. In commonly used dual-staining approaches, membrane-permeant fluorogenic substrates are converted by intracellular esterases into fluorescent products in live cells, while impermeant DNA-binding dyes selectively enter cells with compromised plasma membranes and label nucleic acids in dead or dying cells, enabling discrimination between viable and non-viable populations by fluorescence microscopy or flow cytometry.
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Apoptosis Solutions
Apoptosis is a regulated, generally non-lytic cell-death pathway that removes unwanted, damaged, infected, or abnormal cells through coordinated morphological changes, caspase activation, DNA fragmentation, and membrane remodeling. The intrinsic apoptosis pathway is controlled mainly by mitochondrial outer membrane permeabilization, BCL-2 family proteins, cytochrome c release, apoptosome formation, caspase-9 activation, and downstream executioner caspase-3/7 activation. The extrinsic apoptosis pathway is initiated by death receptors such as Fas, TNFR, and TRAIL receptors, which recruit adaptor proteins and activate caspase-8 before engaging executioner caspases or mitochondrial amplification through BID cleavage. Apoptosis is linked to many phenotypes, including cancer cell killing, tissue homeostasis, immune regulation, neurodegeneration, infection response, and treatment-induced cytotoxicity; unresolved questions include how apoptosis interacts with necroptosis, pyroptosis, ferroptos
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Lysosome and acidic-vesicle live-cell staining
Lysosome and acidic-vesicle live-cell staining detects acidic intracellular compartments by using membrane-permeant acidotropic probes that accumulate in low-pH vesicles, including lysosomes, late endosomes, autolysosomes, and acidic phagosomes. LysoTracker staining is commonly used as an intensity-based readout of acidic lysosomal compartment abundance or enlargement, while acridine orange produces green fluorescence in less concentrated compartments and red fluorescence after concentration-dependent accumulation in acidic vesicular organelles. Loss or reduction of acridine-orange red signal can be used as a readout of lysosomal membrane permeabilization or reduced acidic-vesicle integrity. This protocol is designed for live cultured cells and can be adapted for fluorescence microscopy, high-content imaging, plate-reader readout, or flow cytometry when the selected literature supports the readout. Because these dyes report acidotropic accumulation rather than lysosome identity alone,
Pureza y Documentación
Referencias
[1]. Ruben Z, et al. The susceptibility of various cultured cells to induction of clear cytoplasmic vacuoles by disobutamide[J]. Toxicology in vitro, 1990, 4(4-5): 497-505. [Content Brief]
[3]. Koizumi H, Watanabe M, Numata H, et al. Species differences in vacuolation of the choroid plexus induced by the piperidine-ring drug disobutamide in the rat, dog, and monkey[J]. Toxicology and applied pharmacology, 1986, 84(1): 125-148. [Content Brief]
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Disobutamide Related Classifications
HY-119753 Related Classifications
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Keywords
- Disobutamide
- 68284-69-5
- SC-31828
- SC31828
- SC 31828
- Others
- rat basophilic leukaemia cells
- phospholipidosis
- rat urinary bladder carcinoma cells
- cardiac arrhythmia
- Chinese hamster ovary tumour cells
- mouse fibroblast cells
- cardiac antiarrhythmic properties
- lysosomes
- blood-brain barrier
- choroid plexus epithelial cells
- Inhibitor
- inhibitor
- inhibit