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Umeclidinium bromide (Synonyms: GSK573719)

Catalog No.GC11831

A muscarinic acetylcholine receptor antagonist

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Umeclidinium bromide Chemical Structure

Cas No.: 869113-09-7

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10mM (in 1mL DMSO)
$91.00
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5mg
$81.00
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10mg
$135.00
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25mg
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50mg
$405.00
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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment:

Ligand binding assays with Umeclidinium bromide (GSK573719A) and [3H]-N-methyl scopolamine (0.5 nM) are performed using a scintillation proximity assay for M1, M2, and M3 mAChRs and a filtration assay for M4 and M5 mAChRs. For the scintillation proximity assay assay, membranes are incubated with wheat germ agglutinin beads in 50 mM HEPES buffer, pH 7.4, at 4°C for 30 minutes and then with the radioligand in a 96-well OptiPlate for 2 hours at room temperature in the presence of vehicle (1% DMSO) or GSK573719 (0.01-300 nM). At the end of the incubation, the plates are centrifuged (for 5 minutes at 2000g), and radioactivity is counted. For the filtration assay, membranes (M4 and M5) are similarly incubated in HEPES buffer containing the radioligand for 2 hours at room temperature in the presence of vehicle (1% DMSO) or Umeclidinium bromide (0.03-300 nM). Atropine is used as a reference agent. Reactions are terminated by rapid filtration through GF/C filters (glass microfiber binder free 1.2 μ). Membranes are washed with ice-cold 50 mM HEPES and transferred to scintillation vials. Radioactivity is counted in a Scintillation Counter. Reactions are terminated by rapid filtration. Data are obtained from three independent experiments. Specific binding is determined by subtracting nonspecific binding (using 0.3 μM atropine) from total binding. The inhibition constant (Ki) for Umeclidinium bromide is calculated. Membranes containing M3 mAChRs are also incubated for 2 hours at room temperature with increasing concentrations of [3H]-N-methyl scopolamine (0.08-9.24 nM) in the presence or absence of Umeclidinium bromide (0.2-0.5 nM) in 50 mM HEPES, pH 7.4. Nonspecific binding is determined using 10 μM atropine. The saturation data are converted to a scatchard plot for analysis[1].

Animal experiment:

Mice[1] Age-matched male BALB/c mice (23-25 gm) are pretreated intranasally (50 μL per mouse) with vehicle (0.9% saline) or Umeclidinium bromide at intervals (0.25-48 hours) prior to methacholine challenge, and placed into individual plethysmograph chambers. Fresh air is supplied by bias flow pumps to the chambers. After baseline respiratory [enhanced pause (Penh)] values are collected, the mice received methacholine (30 mg/mL or EC80) by aerosol delivery (flow=1.6 mL/min×2 minutes). An average Penh is then calculated for 5 minutes. Penh=[(expiratory time/relaxation time)−1]×(peak expiratory flow/peak inspiratory flow), and relaxation time is the amount of time required for 70% of the tidal volume to expire. In some cases, animals are treated on multiple, consecutive days as described in the figure legends. The data are expressed as the mean±S.E.M. percent inhibition of Penh or (mean Penh value of vehicle treated group-Penh for each drug-treated animal) divided by (mean Penh value of vehicle treated group)×100%. Data are analyzed using commercially available software.

References:

[1]. Salmon M, et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70.
[2]. Cazzola M, et al. Pharmacology and therapeutics of bronchodilators. Pharmacol Rev. 2012 Jul;64(3):450-504.
[3]. Calzetta L, et al. Pharmacological characterization of the interaction between umeclidinium and vilanterol in human bronchi. Eur J Pharmacol. 2017 Jul 14. pii: S0014-2999(17)30470-3.

Background

Umeclidinium bromide is a potent and long-acting antagonist of muscarinic cholinergic receptor (mAChR) with Ki values of 0.16nM, 0.15nM, 0.06nM, 0.05nM and 0.13nM for M1, M2, M3, M4 and M5, respectively [1].

Umeclidinium bromide is developed for the treatment of chronic obstructive pulmonary disease (COPD). It can help patients of COPD achieve sufficient oxygenation of extrapulmonary tissues through dilating the airways. In the in vitro assay, umeclidinium binds to recombinant human mAChRs with Ki value of 0.16nM, 0.15nM, 0.06nM, 0.05nM and 0.13nM for M1-M5, respectively. Umeclidinium is selective against mAChR over other unrelated receptors or channels such as κ and σ opiod receptors, Na+ channel and dopamine transporter. In CHO cells transfected with human recombinant mAChRs, umeclidinium affects the calcium flux responsed to Ach with pA2 values of 9.6-10.6 for M1-M3. In a murine model, administration of umeclidinium can reverse the bronchoconstriction caused by Ach [1].

References:
[1] Salmon M, Luttmann M A, Foley J J, et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. Journal of Pharmacology and Experimental Therapeutics, 2013, 345(2): 260-270.

Chemical Properties

Cas No. 869113-09-7 SDF
Synonyms GSK573719
Chemical Name diphenyl-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide
Canonical SMILES C1C[N+]2(CCC1(CC2)C(C3=CC=CC=C3)(C4=CC=CC=C4)O)CCOCC5=CC=CC=C5.[Br-]
Formula C29H34BrNO2 M.Wt 508.49
Solubility DMF: 10 mg/ml,DMSO: 15 mg/ml,DMSO:PBS(pH 7.2) (1:3): 0.25 mg/ml,Ethanol: 0.14 mg/ml,PBS (pH 7.2): Inosluble Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 1.9666 mL 9.833 mL 19.6661 mL
5 mM 0.3933 mL 1.9666 mL 3.9332 mL
10 mM 0.1967 mL 0.9833 mL 1.9666 mL
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