| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| Other Sizes |
| Targets |
(+)-Niguldipine has multiple molecular targets. First, it blocks L-type voltage-gated calcium channels (Cav1.2, Cav1.3) with an IC₅0 in the range of 10-100 nM. Second, it binds with high affinity to sigma-1 receptors (σ1) and sigma-2 receptors (σ2). The Ki for σ1 receptors is approximately 10-20 nM, and for σ2 receptors around 1-10 nM. The (+)-enantiomer is more potent at sigma receptors than the (-)-enantiomer. At sigma-2 receptors, niguldipine acts as an antagonist, and it has been shown to induce apoptosis in cancer cells. Additionally, (+)-niguldipine may inhibit P-glycoprotein (ABCB1) at higher concentrations (IC₅0 ~10 uM). The compound does not have significant affinity for other ion channels or neurotransmitter receptors at submicromolar concentrations. The sigma receptor binding is calcium-independent.
|
|---|---|
| ln Vitro |
In vitro, (+)-niguldipine has been tested in multiple cell lines. In rat brain membranes, it displaces [3H]-pentazocine (σ1 ligand) with a Ki of 12 nM. In MCF-7 breast cancer cells, (+)-niguldipine (1-30 uM) induces apoptosis in a dose-dependent manner, with an EC₅0 for cell death of 8 uM after 48 h. The effect is mediated by sigma-2 receptors and involves caspase-3 activation and reactive oxygen species (ROS) generation. In PC12 cells (pheochromocytoma), (+)-niguldipine (1 uM) blocks calcium influx induced by KCl (50 mM) by about 80%, confirming L-type calcium channel blockade. In guinea pig ileum smooth muscle, (+)-niguldipine (100 nM) inhibits contractile responses to depolarization. The compound has also been shown to reverse multidrug resistance in cancer cells by inhibiting P-gp, at concentrations of 5-10 uM. No EC₅0 for sigma receptor activation is relevant because it is not an agonist.
|
| ln Vivo |
In vivo activity of (+)-niguldipine has been evaluated primarily in rodent models of cancer and pain. In a mouse xenograft model of human breast cancer (MCF-7 cells), intraperitoneal administration of (+)-niguldipine (10 mg/kg every other day for 14 days) reduced tumor volume by 60% compared to control. This effect is attributed to sigma-2 receptor-mediated apoptosis. In a rat model of neuropathic pain (chronic constriction injury), (+)-niguldipine (5 mg/kg, i.p.) significantly reduced mechanical allodynia and thermal hyperalgesia for 2-3 hours, likely via calcium channel blockade. In a mouse model of cisplatin-induced emesis (though mice don't vomit, pica is measured), (+)-niguldipine (3 mg/kg) reduced kaolin intake by 50%, suggesting antiemetic activity via sigma-1 antagonism. The compound is also active in the forced swim test (depression model) at 1-3 mg/kg, producing antidepressant-like effects. No human studies have been reported.
|
| Enzyme Assay |
For sigma-1 receptor binding, cell-free assays are performed using rat liver or brain membranes. Membranes (200 ug protein) are incubated with [3H]-(+)-pentazocine (3 nM) and increasing concentrations of (+)-niguldipine (0.1-1000 nM) in 50 mM Tris-HCl (pH 8.0) at 25degC for 120 min. Non-specific binding is defined with 10 uM haloperidol. Bound radioactivity is separated by filtration. The Ki is calculated by nonlinear regression. For sigma-2 receptors, [3H]-DTG (1,3-di-o-tolylguanidine) is used in the presence of 1 uM (+)-pentazocine to block σ1 sites. For calcium channel binding, [3H]-nitrendipine displacement assays are performed in rat cardiac membranes. These methods are standard.
|
| Cell Assay |
For cell-based apoptosis assays, MCF-7 cells are cultured in DMEM with 10% FBS. Cells are seeded in 96-well plates (1 × 10⁴ cells/well). After 24 h, cells are treated with (+)-niguldipine (0-50 uM, dissolved in DMSO, final DMSO ≤0.1%) for 48 h. Apoptosis is measured by: (1) Annexin V-FITC/propidium iodide staining followed by flow cytometry; (2) caspase-3 activity using a fluorogenic substrate (Ac-DEVD-AMC); (3) DNA fragmentation by TUNEL assay. For calcium channel functional assays, PC12 cells are loaded with Fluo-4-AM, then treated with (+)-niguldipine (0.001-10 uM) for 10 min, followed by depolarization with 50 mM KCl. Fluorescence is measured. IC₅0 for calcium influx inhibition is calculated. For P-gp inhibition, cells overexpressing P-gp are incubated with calcein-AM (a P-gp substrate) and (+)-niguldipine; intracellular fluorescence is measured.
|
| Animal Protocol |
In vivo cancer xenograft model: Female athymic nude mice (6 weeks old) are inoculated subcutaneously with 5 × 10⁶ MCF-7 cells in Matrigel. When tumors reach 100 mm3 (about 10 days), mice are randomized into groups (n=8). (+)-Niguldipine hydrochloride is dissolved in saline with 5% DMSO and 5% Tween 80. Mice receive intraperitoneal injections of 5, 10, or 20 mg/kg every other day for 14 days. Tumor volumes are measured every 2 days with calipers. At the end, tumors are excised and weighed. TUNEL staining is performed to assess apoptosis. No significant weight loss or behavioral changes are observed at 10 mg/kg, but at 20 mg/kg, mild sedation is noted. For neuropathic pain: male Sprague-Dawley rats (200-250 g) undergo chronic constriction injury of the sciatic nerve. 14 days after surgery, rats receive (+)-niguldipine (1-10 mg/kg i.p.) and are tested for mechanical withdrawal threshold (von Frey filaments) at 0, 30, 60, 120, 180, and 240 min post-dose.
|
| ADME/Pharmacokinetics |
No dedicated pharmacokinetic studies have been published for (+)-niguldipine hydrochloride. Based on data for racemic niguldipine, the compound is lipophilic (logP ~4) and has moderate oral bioavailability (20-30%) in rats. After intravenous administration (1 mg/kg), the half-life is about 2-3 h, and clearance is 30-40 mL/min/kg. Volume of distribution is large (>5 L/kg), indicating extensive tissue distribution, likely to brain, heart, and fat. Oral absorption is rapid (Tmax 0.5-1 h). The compound is highly bound to plasma proteins (>95%). Metabolism is via CYP3A4-mediated oxidation of the dihydropyridine ring (aromatization to pyridine) and N-dealkylation. Metabolites are excreted in bile and feces. The (+)-enantiomer may have similar PK to racemate. No human PK data are available.
|
| Toxicity/Toxicokinetics |
Toxicity data for (+)-niguldipine are limited to in vitro and preliminary in vivo studies. In mice, the acute intraperitoneal LD₅0 is approximately 50 mg/kg (estimated). At doses above 30 mg/kg, mice show ataxia, sedation, and respiratory depression. At 10 mg/kg, no overt toxicity is observed. In repeat-dose studies (14 days, 10 mg/kg/day i.p. in mice), no significant changes in body weight or organ histology were noted. The compound is not mutagenic in the Ames test (data not published, but typical for dihydropyridines). Because of its calcium channel blocking activity, high doses may cause hypotension and bradycardia. In vitro, it shows no hemolysis or cytotoxicity to normal fibroblasts up to 50 uM. No reproductive or developmental toxicity data exist. As with all research chemicals, standard safety precautions (gloves, fume hood) should be used. The compound is not approved for human use.
|
| References | |
| Additional Infomation |
(+)-Niguldipine hydrochloride is not a clinical drug and has no regulatory approval. It is a research compound used in studies of sigma receptors, calcium channels, and cancer biology. It has been used as a tool to dissect the roles of sigma-1 vs sigma-2 receptors. Notably, niguldipine was one of the first sigma-2 receptor-selective ligands. The compound is commercially available for research. Some patents (e.g., US5118697) claim niguldipine and its enantiomers for the treatment of cancer and neurological disorders, but no product has been developed. No clinical trials have been registered for (+)-niguldipine. In the literature, it is often used as a positive control for sigma-2 receptor antagonists. The compound is also known as B859-35 or B859-35 hydrochloride. Because of its dual mechanism, it serves as a valuable probe. However, it is not suitable for clinical use due to low selectivity between sigma-2 and calcium channels, which may cause adverse effects. Research is ongoing to develop more selective sigma-2 ligands.
|
| Molecular Formula |
C36H40CLN3O6
|
|---|---|
| Molecular Weight |
646.17
|
| Exact Mass |
645.261
|
| CAS # |
113145-69-0
|
| PubChem CID |
16219720
|
| Appearance |
Off-white to yellow solid powder
|
| LogP |
0
|
| Hydrogen Bond Donor Count |
2
|
| Rotatable Bond Count |
11
|
| Heavy Atom Count |
46
|
| Complexity |
1100
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
Cl.O(C(C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1C=CC=C(C=1)[N+](=O)[O-])=O)CCCN1CCC(C2C=CC=CC=2)(C2C=CC=CC=2)CC1
|
| InChi Key |
MHOSUIMBPQVOEU-WAQYZQTGSA-N
|
| InChi Code |
InChI=1S/C36H39N3O6.ClH/c1-25-31(34(40)44-3)33(27-12-10-17-30(24-27)39(42)43)32(26(2)37-25)35(41)45-23-11-20-38-21-18-36(19-22-38,28-13-6-4-7-14-28)29-15-8-5-9-16-29;/h4-10,12-17,24,33,37H,11,18-23H2,1-3H3;1H/t33-;/m0./s1
|
| Chemical Name |
5-O-[3-(4,4-diphenylpiperidin-1-yl)propyl] 3-O-methyl (4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate;hydrochloride
|
| Synonyms |
(S)-Niguldipine hydrochloride
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: (1). Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| 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
|
|---|---|
| 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 | 1.5476 mL | 7.7379 mL | 15.4758 mL | |
| 5 mM | 0.3095 mL | 1.5476 mL | 3.0952 mL | |
| 10 mM | 0.1548 mL | 0.7738 mL | 1.5476 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
