Methylnaltrexone bromide is a novel and potent μ-opioid antagonist.
Physicochemical Properties
| Molecular Formula | C21H26NO4BR |
| Molecular Weight | 436.33944 |
| Exact Mass | 435.105 |
| Elemental Analysis | C, 57.81; H, 6.01; Br, 18.31; N, 3.21; O, 14.67 |
| CAS # | 73232-52-7 |
| PubChem CID | 5361917 |
| Appearance | Typically exists as solid at room temperature |
| Melting Point | 237-239ºC |
| LogP | 3.025 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 2 |
| Heavy Atom Count | 27 |
| Complexity | 664 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | C[N+]1(CC[C@@]23C4=C5C=CC(=C4O[C@H]3C(=O)CC[C@]2([C@H]1C5)O)[O-])CC6CC6.Br |
| InChi Key | IFGIYSGOEZJNBE-KNLJMPJLSA-N |
| InChi Code | InChI=1S/C21H25NO4.BrH/c1-22(11-12-2-3-12)9-8-20-17-13-4-5-14(23)18(17)26-19(20)15(24)6-7-21(20,25)16(22)10-13;/h4-5,12,16,19,25H,2-3,6-11H2,1H3;1H/t16-,19+,20+,21-,22?;/m1./s1 |
| Chemical Name | (4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a,9-dihydroxy-3-methyl-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-3-ium-7-one;bromide |
| Synonyms | MOA-728; MOA728; Methylnaltrexone bromide; Naltrexone methobromide; Relistor; N-Methylnaltrexone Bromide; MRZ-2663BR; bromuro de metilnaltrexona; ...; 73232-52-7; MOA 728 |
| 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 |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
μ-opioid receptor (μOR) with antagonist activity (IC₅₀ = 0.8 nM in radioligand binding assay) |
| ln Vitro |
1. Receptor Binding Assay:
- Methylnaltrexone bromide demonstrated high affinity for μOR in CHO cell membranes expressing human μOR, with Kᵢ = 0.7 nM. Selectivity over δ- and κ-opioid receptors was >100-fold 2. GTPγS Binding Assay: - Inhibited μOR-mediated G protein activation with IC₅₀ = 1.2 nM, confirming antagonist activity |
| ln Vivo |
1. Opioid-Induced Constipation Model:
- In rats with morphine-induced constipation, subcutaneous Methylnaltrexone bromide (0.3 mg/kg) reversed gastrointestinal transit delay without affecting analgesia. The effect persisted for 6-8 hours, with peak activity at 2 hours post-dose 2. Neuroprotection Study: - In a mouse model of ischemic stroke, intraperitoneal Methylnaltrexone bromide (1 mg/kg) reduced infarct volume by 35% and improved neurological scores. This effect was attributed to peripheral μOR antagonism reducing neuroinflammation |
| Enzyme Assay |
1. Radioligand Binding Assay:
- Membranes from CHO cells expressing human μOR were incubated with [³H]-dihydromorphine (0.5 nM) and increasing concentrations of Methylnaltrexone bromide (0.01 nM–10 μM) in Tris-HCl buffer (pH 7.4) at 25°C for 60 minutes. Nonspecific binding was determined using 1 μM naloxone. IC₅₀ values were calculated by nonlinear regression |
| Cell Assay |
- cAMP Inhibition Assay:
- SH-SY5Y cells stably expressing μOR were treated with Methylnaltrexone bromide (0.1 nM–10 μM) followed by stimulation with DAMGO (100 nM). Intracellular cAMP levels were quantified using an enzyme immunoassay. The compound reversed DAMGO-induced cAMP suppression with IC₅₀ = 1.5 nM |
| Animal Protocol |
1. Subcutaneous Administration in Rats:
- Methylnaltrexone bromide was formulated in saline and administered subcutaneously at 0.3 mg/kg to rats with morphine-induced constipation. Gastrointestinal transit was measured by charcoal meal assay. Plasma samples were collected at 0, 0.5, 1, 2, 4, 6, and 8 hours post-dose 2. Intraperitoneal Administration in Mice: - For stroke model, Methylnaltrexone bromide (1 mg/kg) was dissolved in sterile saline and administered intraperitoneally 30 minutes after middle cerebral artery occlusion. Neurological deficits were evaluated using a 5-point scale at 24 hours post-ischemia |
| ADME/Pharmacokinetics |
- Absorption:
- Oral bioavailability in rats was 12%, with peak plasma concentration (Cₘₐₓ) of 25 ng/mL at 1 hour post-dose. Subcutaneous bioavailability was 85% - Metabolism: - Primarily metabolized by hepatic CYP3A4 to inactive conjugates. Less than 5% of the dose was excreted unchanged in urine - Half-life: - Plasma t½ was 3.5 hours in rats, with prolonged receptor occupancy due to slow dissociation from μOR |
| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation No information is available on the use of methylnaltrexone during breastfeeding. The manufacturer recommends avoiding breastfeeding in mothers taking methylnaltrexone. Based on pharmacokinetic data, the oral absorption of methylnaltrexone appears to be very low. Observe breastfed infants who have been exposed to opioids during pregnancy or postpartum for signs of opioid withdrawal, especially diarrhea. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. - Acute Toxicity: - LD₅₀ in mice exceeded 2000 mg/kg (oral), with no signs of organ toxicity in histopathological analysis - Plasma Protein Binding: - 92% bound to plasma proteins in human serum, which may influence distribution and clearance |
| References |
[1]. J Cell Physiol. 2021 Nov;236(11):7698-7710. Hyperlink: https://pubmed.ncbi.nlm.nih.gov/34038587/ [2]. Neuropharmacology. 2021 Mar 1;185:108437. Hyperlink: https://pubmed.ncbi.nlm.nih.gov/33316279/ |
| Additional Infomation |
- Background:
- Methylnaltrexone bromide is a quaternary amine derivative of naltrexone, designed to minimize blood-brain barrier penetration. It is clinically approved for opioid-induced constipation in patients with advanced illness - Mechanism: - Competitive antagonist at peripheral μOR, blocking opioid-induced gastrointestinal effects without reversing analgesia. Its long duration of action is attributed to slow off-rate from the receptor - Clinical Potential: - Phase III trials demonstrated safety and efficacy in reducing opioid-induced constipation with minimal systemic side effects. However, cases of gastrointestinal perforation have been reported in patients with advanced illness |
Solubility Data
| 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 (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *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). 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)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL 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). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2918 mL | 11.4590 mL | 22.9179 mL | |
| 5 mM | 0.4584 mL | 2.2918 mL | 4.5836 mL | |
| 10 mM | 0.2292 mL | 1.1459 mL | 2.2918 mL |