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MG624 (MG-624) is a novel and potent antagonist of neuronal nicotinic acetylcholine receptors (Ki = 106 nM), it can decrease vagus nerve stimulation-induced contractions of isolated guinea pig vagus nerve-stomach preparations.
| Targets |
nAChR/nicotinic acetylcholine receptors
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|---|---|
| ln Vitro |
In this study, researchers assessed the pharmacological activity of triethyl-(β-4-stilbenoxy-ethyl) ammonium (MG624), a drug that is active on neuronal nicotinic receptors (nicotinic AChR). Experiments on the major nicotinic AChR subtypes present in chick brain, showed that it inhibits the binding of [125I]-αBungarotoxin (αBgtx) to the α7 subtype, and that of [3H]-epibatidine (Epi) to the α4β2 subtype, with Ki values of respectively 106 nm and 84 μm.[1]
MG624 also inhibited ACh elicited currents (IACh) in the oocyte-expressed α7 and α4β2 chick subtypes with half-inhibitory concentrations (IC50) of respectively 109 nm and 3.2 μm.[1] When tested on muscle-type AChR, it inhibited [125I]-αBgtx binding with a Ki of 32 μm and ACh elicited currents (IACh) in the oocyte-expressed α1β1γδ chick subtype with an IC50 of 2.9 μm.[1] The interaction of MG624 with the α7 subtype was investigated using an α7 homomeric mutant receptor with a threonine-for-leucine 247 substitution (L247T α7). MG624 did not induce any current in oocytes expressing the wild type α7 receptor, but did induce large currents in the oocyte-expressed L247T α7 receptor. The MG624 elicited current (IMG624) has an EC50 of 0.2 nm and a Hill coefficient nH of 1.9, and is blocked by the nicotinic receptor antagonist methyllycaconitine (MLA).[1] These binding and electrophysiological studies show that MG624 is a potent antagonist of neuronal chick α7 nicotinic AChR, and becomes a competitive agonist following the mutation of the highly conserved leucine residue 247 located in the M2 channel domain.[1] |
| ln Vivo |
The administration of 20 μM MG624 attenuated the nicotine-induced angiogenesis of H69 human SCLC tumors (implanted on CAM) by approximately 50%, as compared to control H69 tumors treated with nicotine only.[2]
MG624 inhibited the growth of human SCLC tumors implanted in nude mice (Fig. 4b). One of our concerns was whether MG624 would cause any side effects in these mice. We observed that the administration of 50 mg MG624/kg food in the diet was well tolerated and there was no sign of discomfort or change in food intake (mean = 5.6 g/day/mouse for both diets), water consumption (vehicle treated mean = 29.0 mL/week/mouse; MG624 treated mean = 29.2 mL/week/mouse) or body weights (vehicle treated mean = 28.1 g/mouse; MG624 treated mean = 27.9 g/mouse) in mice administered nicotine and/or MG624. Immunohistochemical staining of tumor sections showed decreased staining of angiogenic markers, namely CD31 and von Willebrand Factor (vWF), in the MG624-treated tumors as compared to the tumors isolated from nicotine-treated mice[2]. |
| Enzyme Assay |
Binding of nicotinic ligands to immobilized subtypes[1]
In order to assess the pharmacological profiles of the immuno-immobilized subtypes we performed competition experiments using MG624, d-Tubocurarine (d-Tub) and MLA. The drugs were dissolved in buffer C just before use and serial dilutions were preincubated for 30 min at RT. Subsequently a final concentration of 0.1 nm [3H]-Epi was added to the α4β2 subtype, and a final concentration of 0.5 nm or 0.3 nm of [125I]-αBgtx was added to the α7 or α1β1γδ subtypes. The α4β2 and α7 subtypes were incubated overnight at 20°C, the α1β1γδ subtype was incubated for 48 h at 20°C. After incubation, the wells were washed seven times with ice-cold PBS containing 0.05% Tween 20, and the bound radioactivity was recovered by means of incubation with 200 μl of 2N NaOH for 2 h. The bound radioactivity was then determined by means of liquid scintillation counting in a β counter in the case of [3H]-Epi, or direct counting in a γ counter in the case of [125I]-αBgtx. |
| Cell Assay |
BrdU proliferation assays[2]
HMEC-Ls were plated in 96-well plates at a density of 10,000 cells/well and rendered quiescent in EGM-R media for 24 h. After 24 h, these cells were treated with 100 nM nicotine for 18 h (which is the time required for S-phase entry) in the presence or absence of varying concentrations of MG624. The rate of BrdU incorporation was measured by the BrdU ELISA kit, according to manufacturer’s instructions. The absorbance of nicotine-treated cells was assumed to be 100%. MG624-induced decreases in the number of cells in S-phase were calculated as a percentage of the nicotine-treated cells. Each sample was tested in duplicate, and the BrdU assay was performed 2 independent times. PCNA cell proliferation assays[2] The effect of MG624 on HMEC-L proliferation was also examined by measuring the levels of proliferating cell nuclear antigen (PCNA). HMEC-Ls were plated in 6-well plates at a density of 250,000 cells/well and treated in an identical manner as in the BrdU assay. The level of PCNA in the cell lysate was quantified by using a PCNA ELISA kit, according to manufacturer’s protocols. Each sample was tested in duplicate, and the assay was performed 2 independent times. |
| Animal Protocol |
Antitumor studies in nude mice[2]
Fourteen 4-week-old male nude mice were acclimatized for 1 week. H69 cells were harvested and re-suspended in a 1:1 (v/v) solution of serum-free RPMI and Matrigel matrix. Two million cells in 100 μL were injected subcutaneously between the scapulae of each mouse. After the tumors reached 100 mm3, the mice were randomized into 2 groups. The control group (n = 7) was fed AIN-76A diet containing vehicle [0.01% DMSO and 10% corn oil]. The treatment group (n = 7) was changed to an AIN76A diet containing 50 mg MG624/kg food (approximately 10 mg MG624/kg body weight of mouse per day). Both of the groups were administered 200 μg/mL nicotine in the drinking water containing 2% saccharin sodium. The food was changed and monitored daily. Nicotine-containing water was changed weekly and monitored daily. Mice were weighed once per week. The administration of MG624 caused no discomfort, lethargy or weight loss in mice. Additionally, food intake and water consumption was similar between control and MG624-treated mice. |
| Toxicity/Toxicokinetics |
Mouse LD50 intraperitoneal 28 mg/kg
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| References | |
| Additional Infomation |
Small cell lung cancer (SCLC) demonstrates a strong etiological association with smoking. Although cigarette smoke is a mixture of about 4,000 compounds, nicotine is the addictive component of cigarette smoke. Several convergent studies have shown that nicotine promotes angiogenesis in lung cancers via the α7-nicotinic acetylcholine receptor (α7-nAChR) on endothelial cells. Therefore, we conjectured that α7-nAChR antagonists may attenuate nicotine-induced angiogenesis and be useful for the treatment of human SCLC. For the first time, our study explores the anti-angiogenic activity of MG624, a small-molecule α7-nAChR antagonist, in several experimental models of angiogenesis. We observed that MG624 potently suppressed the proliferation of primary human microvascular endothelial cells of the lung (HMEC-Ls). Furthermore, MG624 displayed robust anti-angiogenic activity in the Matrigel, rat aortic ring and rat retinal explant assays. The anti-angiogenic activity of MG624 was assessed by two in vivo models, namely the chicken chorioallantoic membrane model and the nude mice model. In both of these experimental models, MG624 inhibited angiogenesis of human SCLC tumors. Most importantly, the administration of MG624 was not associated with any toxic side effects, lethargy or discomfort in the mice. The anti-angiogenic activity of MG624 was mediated via the suppression of nicotine-induced FGF2 levels in HMEC-Ls. MG624 decreased nicotine-induced early growth response gene 1 (Egr-1) levels in HMEC-Ls, and reduced the levels of Egr-1 on the FGF2 promoter. Consequently, this process decreased FGF2 levels and angiogenesis. Our findings suggest that the anti-angiogenic effects of MG624 could be useful in anti-angiogenic therapy of human SCLCs.[2]
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| Molecular Formula |
C22H30INO
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|---|---|
| Molecular Weight |
451.3925
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| Exact Mass |
324.233
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| Elemental Analysis |
C, 58.54; H, 6.70; I, 28.11; N, 3.10; O, 3.54
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| CAS # |
77257-42-2
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| PubChem CID |
6433339
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| Appearance |
White to off-white solid powder
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| LogP |
5.112
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
25
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| Complexity |
339
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC[N+](CC)(CC)CCOC1=CC=C(C=C1)/C=C/C2=CC=CC=C2.[I-]
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| InChi Key |
RDTKUZXIHMTSJO-UEIGIMKUSA-M
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| InChi Code |
InChI=1S/C22H30NO.HI/c1-4-23(5-2,6-3)18-19-24-22-16-14-21(15-17-22)13-12-20-10-8-7-9-11-20;/h7-17H,4-6,18-19H2,1-3H3;1H/q+1;/p-1/b13-12+;
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| Chemical Name |
triethyl-[2-[4-[(E)-2-phenylethenyl]phenoxy]ethyl]azanium;iodide
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| Synonyms |
MG-624; MG 624; Stilonium iodide; MG 624; 77257-42-2; MG624; MG-624; 2551-76-0; M.G. 624; DTXSID2045781; MG624
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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 Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), 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)
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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 | 2.2154 mL | 11.0769 mL | 22.1538 mL | |
| 5 mM | 0.4431 mL | 2.2154 mL | 4.4308 mL | |
| 10 mM | 0.2215 mL | 1.1077 mL | 2.2154 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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