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Purity: ≥98%
Alvimopan (also known as ADL 8-2698; LY 246736; HSDB-7704) is a novel peripheral micro opioid antagonist in clinical development for the management of post-operative ileus and opioid-induced bowel dysfunction. Alvimopan acts for a longer period of time than other antagonists that act more quickly, which may be connected to a slower rate of dissociation from the micro opioid receptor. In comparison to the long-acting partial agonist buprenorphine (t(1/2)=44 min), alvimopan's dissociation rate from the micro opioid receptor (t(1/2)=30–44 min) was slower than that of the antagonists naloxone (t(1/2)=0.82 min) and N-methylnaltrexone (t(1/2)=0.46 min). Moreover, after preincubation with the micro opioid receptor, increases were seen in the apparent affinities and potencies of buprenorphine and alvimopan, but not of naloxone or methylnaltrexone. Alvimopan does not dissociate from the micro opioid receptor as quickly as other drugs that act more quickly, which is consistent with its prolonged duration of action.
| Targets |
μ Opioid Receptor/MOR
μ-Opioid Receptor (Ki=0.6 nM in human recombinant μ-opioid receptor binding assay) [1] κ-Opioid Receptor (Ki=125 nM in human recombinant κ-opioid receptor binding assay) [1] δ-Opioid Receptor (Ki=410 nM in human recombinant δ-opioid receptor binding assay) [1] |
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| Enzyme Assay |
Alvimopan has a more modest (≥6-fold) μ/δ receptor selectivity, but is highly selective (by ≥227-fold) for the human μ receptor over the κ subtype. Alvimopan has pA2 values of 9.6 or 9.7 and is a strong antagonist of morphine, DAMGO or endomorphin-1-induced, and μ opioid receptor-mediated electrically evoked contraction inhibition in the isolated ileum of guinea pigs. The ileum of guinea pigs has lower alvimopan antagonist potencies (δ and κ antagonists, with pA2 values of 8.7 and 7.8, respectively). Tested at both 1 and 10 μM, alvimopan does not exhibit any noteworthy affinity for a wide variety of non-opioid receptors, ion channels, or enzymes.
μ-Opioid receptor binding assay (radioligand competition): Human recombinant μ-, κ-, δ-opioid receptor-expressing cell membranes are suspended in binding buffer (50 mM Tris-HCl pH 7.4, 10 mM MgCl₂, 1 mM EDTA, 0.1% BSA). Serial 3-fold dilutions of Alvimopan monohydrate (0.001–1000 nM) are mixed with membrane suspension and [³H]-DAMGO (μ-opioid agonist, final concentration 0.4 nM) or [³H]-U69593 (κ-agonist, 0.5 nM) or [³H]-DPDPE (δ-agonist, 0.5 nM). The mixture is incubated at 25°C for 90 minutes, then filtered through glass fiber filters to separate bound and free ligand. Filters are washed with ice-cold binding buffer, and radioactivity is measured by liquid scintillation counting. Ki values are calculated using the Cheng-Prusoff equation [1] - Opioid-induced signaling inhibition assay: μ-opioid receptor-expressing CHO cells are pre-treated with Alvimopan monohydrate (0.01–100 nM) for 30 minutes, then stimulated with DAMGO (100 nM) to induce cAMP accumulation inhibition. cAMP levels are measured by ELISA, and IC₅₀ values for inhibition of DAMGO-mediated signaling are calculated [1] |
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| Cell Assay |
Blood-brain barrier penetration assay: Artificial BBB models are established by co-culturing human brain microvascular endothelial cells and astrocytes in transwell inserts. Alvimopan monohydrate (0.1–1 μM) is added to the apical chamber (simulating bloodstream), and samples are collected from the basolateral chamber (simulating CNS) at 1, 2, and 4 hours. Drug concentration is quantified by HPLC-MS/MS, and permeability coefficient (Papp) is calculated to assess BBB penetration [2]
- Gastrointestinal smooth muscle cell contraction assay: Primary guinea pig ileum smooth muscle cells are isolated and seeded in 96-well plates. Cells are pre-treated with Alvimopan monohydrate (1–100 nM) for 30 minutes, then stimulated with fentanyl (1 μM) and acetylcholine (10 μM). Cell contraction is measured by impedance-based assay, and the reversal rate of fentanyl-induced inhibition is calculated [3] |
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| Animal Protocol |
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| ADME/Pharmacokinetics |
Oral bioavailability: 11–16% in humans (12 mg dose), 13% in rats (1 mg/kg orally), and 17% in dogs (0.5 mg/kg orally) [2]
- Plasma pharmacokinetics: In humans, oral administration of 12 mg avimopan monohydrate yielded Cmax = 1.3 ng/mL, AUC₀–24h = 7.2 ng·h/mL, and terminal half-life (t₁/₂) = 11–18 hours [2] - In rats, oral administration of 1 mg/kg yielded Cmax = 0.9 ng/mL, AUC₀–24h = 4.8 ng·h/mL, and t₁/₂ = 9.2 hours [2] - Tissue distribution: Primarily distributed in peripheral tissues (intestinal wall, liver, kidneys); in rats and dogs, the central nervous system concentration was less than 1% of the plasma concentration. [2] - Metabolism: It is metabolized very little in the human body (about 6% of the dose), mainly through glucuronidation to generate the inactive metabolite M1; it does not involve cytochrome P450-mediated metabolism.[2] - Excretion: 72-hour cumulative excretion: 71% is excreted in feces (68% of which is the original drug), and 24% is excreted in urine (18% of which is the original drug and 6% is M1).[2] - Plasma protein binding rate: 81–86% in human plasma, 79–84% in rat plasma, and 82–87% in canine plasma (balanced dialysis, 0.1–10 ng/mL).[2] |
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| Toxicity/Toxicokinetics |
Acute toxicity (mice): Oral LD₅₀ > 5000 mg/kg; no death or serious toxicity was observed at doses up to 5000 mg/kg [2]
- Subchronic toxicity (rats, 28 days): No significant changes were observed in body weight, food intake, hematological parameters (erythrocytes, leukocytes, platelets) or biochemical markers (ALT, AST, BUN, creatinine) at oral doses up to 100 mg/kg/day; no abnormalities were observed in liver, kidney, intestinal or brain tissue pathology [2] - Chronic toxicity (dogs, 90 days): 12% of dogs experienced mild, transient diarrhea at oral doses up to 50 mg/kg/day; no other toxic effects were observed [2] - Adverse reactions in humans: The most common treatment-related adverse events were gastrointestinal reactions (abdominal pain: 9-13%, diarrhea: 7-11%, nausea: 5-7%); rare adverse events included headache (2-4%), dizziness (1-3%) and flatulence (1-2%); there was no significant hepatotoxicity, nephrotoxicity or central nervous system depression [2] - Drug interactions: It does not inhibit or induce CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4); there were no clinically relevant interactions with opioids, anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs) or anticoagulants [2] |
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| References |
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| Additional Infomation |
Avimopan monohydrate is the monohydrate form of avimopan, a peripherally acting μ-opioid receptor antagonist used to prevent postoperative intestinal obstruction (POI) and treat opioid-induced constipation (OIC) [2]
- Its mechanism of action involves competitive binding to peripheral μ-opioid receptors (mainly located in the gastrointestinal tract), reversing opioid-induced gastrointestinal motility and secretion inhibition, and does not cross the blood-brain barrier, thus preserving opioid-mediated analgesia [1][2] - The monohydrate form maintains the same pharmacological activity and selectivity as the anhydrous form, and its water solubility is improved, which is beneficial for the development of oral formulations [1] - Clinical efficacy: In a phase III clinical trial, Avimopan monohydrate (12 oz orally 1 hour before surgery) mg, followed by 12 mg once daily for up to 7 days, can shorten the time to first defecation by 14-26 hours and the length of hospital stay by 1-2 days in patients undergoing colorectal surgery[2] - FDA-approved indications: prevention of postoperative bowel obstruction in patients undergoing colorectal surgery; treatment of opioid-induced constipation in adult patients with chronic non-cancer pain treated with opioids[2] - Recommended dose: prevention of postoperative bowel obstruction: 12 mg orally 1 hour before surgery, followed by 12 mg once daily for up to 7 days (up to 15 doses); treatment of opioid-induced constipation: 12 mg once daily[2] - Contraindications: patients with known hypersensitivity to avimopan or any of its components; patients who have received therapeutic doses of opioids for more than 7 consecutive days prior to treatment (risk of opioid withdrawal symptoms)[2] |
| Molecular Formula |
C25H34N2O5
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|---|---|
| Molecular Weight |
442.56
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| Exact Mass |
442.247
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| Elemental Analysis |
C, 67.85; H, 7.74; N, 6.33; O, 18.08
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| CAS # |
1383577-62-5
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| Related CAS # |
Alvimopan dihydrate; 170098-38-1; Alvimopan; 156053-89-3
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| PubChem CID |
71587995
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| Appearance |
White to off-white solid powder
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| LogP |
3.765
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
32
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| Complexity |
606
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| Defined Atom Stereocenter Count |
3
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| SMILES |
OC1=CC=CC([C@@]2(C)[C@@H](C)CN(C[C@H](CC3=CC=CC=C3)C(NCC(O)=O)=O)CC2)=C1.O
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| InChi Key |
XSTFUWQLHMJPFG-NABRLNOVSA-N
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| InChi Code |
InChI=1S/C25H32N2O4.H2O/c1-18-16-27(12-11-25(18,2)21-9-6-10-22(28)14-21)17-20(24(31)26-15-23(29)30)13-19-7-4-3-5-8-19;/h3-10,14,18,20,28H,11-13,15-17H2,1-2H3,(H,26,31)(H,29,30);1H2/t18-,20-,25+;/m0./s1
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| Chemical Name |
2-[[(2S)-2-benzyl-3-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]propanoyl]amino]acetic acid;hydrate
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| Synonyms |
LY246736 monohydrate; LY246736; LY-246736; HSDB 7704; HSDB7704 monohydrate; HSDB-7704; ADL 8-2698; ADL8-2698; ADL-8-2698 monohydrate;Alvimopan monohydrate. Brand name: Entereg
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| HS Tariff Code |
2934.99.03.00
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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) |
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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 | 2.2596 mL | 11.2979 mL | 22.5958 mL | |
| 5 mM | 0.4519 mL | 2.2596 mL | 4.5192 mL | |
| 10 mM | 0.2260 mL | 1.1298 mL | 2.2596 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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