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| Targets |
5-(N,N-Hexamethylene)-amiloride targets Na+/H+ exchangers (NHEs), particularly NHE1, and acid-sensing ion channels (ASICs). It also inhibits the HIV-1 Vpu virus ion channel and shows antiviral activity against mouse hepatitis virus (MHV) and human coronavirus 229E (HCoV-229E). The compound induces apoptosis in leukemic cells by decreasing intracellular pH. It is a potent inhibitor of sodium-hydrogen antiporters.
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| ln Vitro |
5-(N,N-hexamethylene)-amiloride inhibits human cardiac ion channels hERG (in CHO cells), Nav1.5, and Cav1.2 (in EHK293 cells) in electrophysiological assays. The concentrations of the inhibitors are 3.3 μM, 30 μM, and 8.3 μM, respectively [3]. At 1 μM, it demonstrated microsomal stability [3]. At 1 μg/mL, it demonstrated mouse plasma stability and plasma protein binding [4–6 hours at 37 °C]. At 20 μM, it demonstrated Caco-2 cell permeability and cardiac ion channel activity [4–6 hours at 37 °C].
In vitro, 5-(N,N-Hexamethylene)-amiloride inhibits Na+/H+ exchange and decreases intracellular pH, leading to apoptosis in leukemic cells. It inhibits HIV-1 Vpu ion channel activity. The compound shows antiviral activity against mouse hepatitis virus (MHV) with an EC₅0 of 3.91 microM and human coronavirus 229E (HCoV-229E) with an EC₅0 of 1.34 microM in cultured L929 cells. It is also a potent inhibitor of acid-sensing ion channels. |
| ln Vivo |
5-(N,N-hexamethylene)-amiloride (2.5 mg/kg; intravenous injection; single dose) has a limited oral bioavailability of 4.5% and a short half-life [3]. Rat or mouse in vivo pharmacokinetic models [3]. The dosage is 2.5 mg/kg. Single-dose intravenous injection administered 10 and 60 minutes following treatment. t1/2 (hour) (mL/min/kg) Plasma CLint Vss of Plasma (L/kg) (h·μM) Plasma AUC0-inf B/P percentage CL of blood (mL/min/kg) Blood Volume (L/kg) ) Mouse, female Balb/c 0.62-86 2.0 1.559 1.4 1.5 The Dawley rat Sprague urine excreted from an IV dose (0–24 hours): 3.2 83.5 5.3 1.6 1.8 46.2 2.9% (mL/min/kg) for renal blood CL CL of non-renal blood (mL/min/kg) Rat Spraggle Dawley 0.5 0.2 46.0 Note: Female Balb/c mouse (17–27 g, non-fasting); male Sprague Dawley Rats (238–325 g, overnight fasting); B/P is the distribution ratio of blood to plasma.
In vivo activity data for 5-(N,N-Hexamethylene)-amiloride are not extensively documented. The compound is primarily used as a research tool for studying ion channel function, pH regulation, and virus-host interactions. Based on its mechanism as an NHE inhibitor, it may have potential effects on acid-base balance and cellular pH homeostasis. Further in vivo studies would be needed to characterize its pharmacokinetic and efficacy profile. |
| Enzyme Assay |
The in vitro enzyme/ion channel inhibition assay for NHE1 typically uses cells expressing the Na+/H+ exchanger. Intracellular pH is measured using pH-sensitive fluorescent dyes (such as BCECF-AM) after acid loading. Cells are acidified by ammonium chloride prepulse, and the rate of pH recovery (which reflects NHE activity) is measured in the presence of varying concentrations of the compound. IC₅0 values are calculated from dose-response curves. For ASIC inhibition, patch-clamp electrophysiology is used to measure ion channel currents.
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| Cell Assay |
Cell Viability Assay[3]
Cell Types: In vitro pharmacokinetic properties Tested Concentrations: 1 μM Incubation Duration: 0-60 minutes Experimental Results: t1/2 (min) CLint (μL/min/mg protein) CLint (μL/min/mg Protein) Human liver microsomes in vitro 73 24 74 Mouse liver microsomes in vitro 2.4 726 2243 For in vitro cell-based assays, leukemic cells or L929 cells are cultured and treated with 5-(N,N-Hexamethylene)-amiloride at various concentrations. Cell viability is measured using MTT or other proliferation assays to assess apoptosis induction. Intracellular pH is measured using fluorescent pH indicators such as BCECF-AM. For antiviral assays, virus-infected cells are treated with the compound and viral replication is quantified by plaque assay or RT-PCR. Experiments are typically performed in triplicate. |
| Animal Protocol |
In vivo animal studies for 5-(N,N-Hexamethylene)-amiloride are not extensively documented. As an ion channel inhibitor, potential in vivo studies would involve mouse models to assess the compound's effects on pH regulation, cardiac function, or viral infection. The compound could be administered via intraperitoneal or intravenous injection. Standard endpoints would include physiological measurements (blood pH, electrolyte levels) and viral load quantification in infection models.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of 5-(N,N-Hexamethylene)-amiloride are not extensively documented. The compound has molecular weight 311.77 and molecular formula C12H1₈ClN₇O. It is soluble in DMSO at 100 mg/mL (320.75 mM). For in vivo formulations, solutions can be prepared in 10% DMSO with 40% PEG300, 5% Tween-80, and 45% saline (≥2.08 mg/mL). Storage: powder at -20degC for 3 years or -80degC in solvent for 6 months. Purity is typically ≥98%.
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| Toxicity/Toxicokinetics |
Toxicological data for 5-(N,N-Hexamethylene)-amiloride are not well characterized. As a research chemical, standard safety precautions should be observed. The compound is for laboratory use only and not intended for human therapeutic applications. Resistance to amiloride derivatives can develop through mutations in SLC9A1 (such as D267N, G455R) that stabilize transporter conformation and reduce inhibitor access. Cross-resistance is observed among amiloride derivatives.
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| References |
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| Additional Infomation |
5-(N,N-hexamethylene)amiloride belongs to the pyrazine class of compounds. Its structure is similar to amiloride, except that the two amino hydrogens at the N-5 position are replaced by hexamethylene groups, forming a nitrogen-containing heptane ring. It possesses various activities, including sodium channel blocker, apoptosis inducer, antitumor agent, and olfactory receptor antagonist. It belongs to the pyrazine, organochlorine, nitrogen-containing heptane, guanidine, aromatic amine, and monocarboxylic acid amide classes. Its function is related to that of amiloride.
5-(N,N-Hexamethylene)-amiloride (CAS# 1428-95-1) is an amiloride derivative also known as Hexamethylene amiloride or HMA. It is used in ion channel regulation studies, host-virus interaction analysis, antiviral screening, and membrane potential modulation research. The compound inhibits Na+/H+ exchange and aids in research on virus-induced pH-dependent entry mechanisms. It is not approved for clinical use. |
| Molecular Formula |
C₁₂H₁₈CLN₇O
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|---|---|
| Molecular Weight |
311.77
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| Exact Mass |
311.126
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| CAS # |
1428-95-1
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| PubChem CID |
1794
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.63g/cm3
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| Boiling Point |
638.2ºC at 760mmHg
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| Flash Point |
339.8ºC
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| Vapour Pressure |
3.47E-16mmHg at 25°C
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| Index of Refraction |
1.742
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| LogP |
2.553
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
21
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| Complexity |
393
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
RQQJJXVETXFINY-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C12H18ClN7O/c13-8-10(20-5-3-1-2-4-6-20)18-9(14)7(17-8)11(21)19-12(15)16/h1-6H2,(H2,14,18)(H4,15,16,19,21)
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| Chemical Name |
3-amino-5-(azepan-1-yl)-6-chloro-N-(diaminomethylidene)pyrazine-2-carboxamide
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| Synonyms |
Hexamethylene amiloride HMA
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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 (~320.75 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (6.67 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.67 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (6.67 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2075 mL | 16.0375 mL | 32.0749 mL | |
| 5 mM | 0.6415 mL | 3.2075 mL | 6.4150 mL | |
| 10 mM | 0.3207 mL | 1.6037 mL | 3.2075 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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