 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C20H25N3O2 |
| Molecular Weight | 339.43 |
| Exact Mass | 339.194 |
| CAS # | 113-42-8 |
| PubChem CID | 8226 |
| Appearance |
Prisms from methanol, acetone Shiny crystals from benzene |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 638.4±55.0 °C at 760 mmHg |
| Melting Point | 172ºC |
| Flash Point | 339.9±31.5 °C |
| Vapour Pressure | 0.0±2.0 mmHg at 25°C |
| Index of Refraction | 1.665 |
| LogP | 1.67 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 25 |
| Complexity | 549 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | CC[C@H](NC([C@H]1CN(C)[C@@]2(CC3=CNC4C3=C(C=CC=4)C2=C1)[H])=O)CO |
| InChi Key | UNBRKDKAWYKMIV-QWQRMKEZSA-N |
| InChi Code | InChI=1S/C20H25N3O2/c1-3-14(11-24)22-20(25)13-7-16-15-5-4-6-17-19(15)12(9-21-17)8-18(16)23(2)10-13/h4-7,9,13-14,18,21,24H,3,8,10-11H2,1-2H3,(H,22,25)/t13-,14+,18-/m1/s1 |
| Chemical Name | (6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide |
| 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 | 5-HT2B Receptor |
| ln Vivo | Thirty minutes after dosing, methylergometrine (0.2 mg/kg; IV; single dose) has mean concentrations of 34 ng/g, 80 ng/g, and 203 ng/g in the uterus, liver, and kidneys of domestic rabbits [3]. Methylergometrine's pharmacokinetic (PK) parameters in rabbits [3] = CO ng/mL K12/min K21/min Ke1/min mean 755.3 0.577 0.180 0.140 SD 215.8 0.098 0.036 0.069 T1/2α/min T1/2β/min Vdc L/kg Vdss L/kg Vdβ L/kg AUCtot (ng/mL)·min CLtot mL/min mean 0.91 26.34 0.29 1.13 1.44 6060.88 83.74 SD 0.35 9.48 0.09 0.30 0.55 2005.30 17.86 |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Absorption is rapid after oral (60% bioavailability) and intramuscular (78% bioavailability) administration. Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver. 56.1 ± 0 L A delayed gastrointestinal absorption (Tmax about 3 hours) of methylergonovine tablets might be observed in postpartum women during continuous treatment with this oxytocic agent. Pharmacokinetic studies following an iv injection have shown that methylergonovine is rapidly distributed from plasma to peripheral tissues within 2-3 minutes or less. The bioavailability after oral administration was reported to be about 60% with no accumulation after repeated doses. During delivery, with intramuscular injection, bioavailability increased to 78%. Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver. Bioavailability studies conducted in fasting healthy female volunteers have shown that oral absorption of a 0.2 mg methylergonovine tablet was fairly rapid with a mean peak plasma concentration of 3243 +/- 1308 pg/mL observed at 1.12 +/- 0.82 hours. For a 0.2 mg intramuscular injection, a mean peak plasma concentration of 5918 +/- 1952 pg/mL was observed at 0.41 +/- 0.21 hours. The extent of absorption of the tablet, based upon methylergonovine plasma concentrations, was found to be equivalent to that of the i.m. solution given orally, and the extent of oral absorption of the i.m. solution was proportional to the dose following administration of 0.1, 0.2, and 0.4 mg. For more Absorption, Distribution and Excretion (Complete) data for METHYLERGONOVINE (15 total), please visit the HSDB record page. Metabolism / Metabolites Hepatic, with extensive first-pass metabolism. Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver. Hepatic, with extensive first-pass metabolism. Route of Elimination: Ergot alkaloids are mostly eliminated by hepatic metabolism and excretion, and the decrease in bioavailability following oral administration is probably a result of first-pass metabolism in the liver. Half Life: 3.39 hours Biological Half-Life 3.39 hours The plasma level decline was biphasic with a mean elimination half-life of 3.39 hours (range 1.5 to 12.7 hours). Plasma concentrations of methylergonovine appear to decline in a biphasic manner. Following IV administration of methylergonovine to adults with normal renal function, the half-life of the drug in the initial phase (t1/2 alpha?) reportedly ranges from about 1-5 minutes and the half-life in the terminal phase (t1/2 beta) ranges from about 0.5-2 hours. |
| Toxicity/Toxicokinetics |
Toxicity Summary Ergoline alkaloids have been shown to have the significant affinity towards the 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and alpha-adrenergic receptors. This can result in a number of different effects, including vasoconstriction, convulsions, and hallucinations. (A2914, A2915, A2916) Interactions Caffeine enhances action of ergot alkaloids in treatment of migraine... /Ergot alkaloids/ Peripheral and coronary vasoconstriction may be antagonized by nitrites or papaverine. /Ergot alkaloids/ Concomitant use of methylergonovine and inhibitors of cytochrome (CYP) 3A4 may result in vasospasm, cerebral ischemia, and/or ischemia of the extremities. Concomitant use of ergot alkaloids and human immunodeficiency virus (HIV) protease inhibitors, delavirdine, or nevirapine is contraindicated. Intravenous atropine sulphate following methylergonovine maleate administration may lead to severe hypertension and tachycardia. Non-Human Toxicity Values LD50 Mouse iv 85 mg/kg LD50 Rabbit iv 2600 mg/kg LD50 Mouse oral 187 mg/kg LD50 Rat iv 23 mg/kg LD50 Rat oral 93 mg/kg |
| References |
[1]. Hajjo R, et al. Development, validation, and use of quantitative structure-activity relationship models of 5-hydroxytryptamine (2B) receptor ligands to identify novel receptor binders and putative valvulopathic compounds among common drugs. J Med Chem. 2010 Nov 11;53(21):7573-86. [2]. Amant F, et al. Misoprostol compared with methylergometrine for the prevention of postpartum haemorrhage: a double-blind randomised trial. Br J Obstet Gynaecol. 1999 Oct;106(10):1066-70. [3]. Mäntylä R, et al. Plasma and tissue concentrations of methylergometrine (methylergonovine) in the rabbit. Acta Pharmacol Toxicol (Copenh). 1980 Apr;46(4):245-9. |
| Additional Infomation |
(6aR,9R)-N-[(2S)-1-hydroxybutan-2-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide is an ergoline alkaloid. A homolog of ergonovine containing one more CH2 group. (Merck Index, 11th ed) Methylergonovine is an Ergot Derivative. Methylergonovine has been reported in Bos taurus with data available. Methylergonovine is only found in individuals that have used or taken this drug. It is a homolog of ergonovine containing one more CH2 group (Merck Index, 11th ed). Methylergonovine acts directly on the smooth muscle of the uterus and increases the tone, rate, and amplitude of rhythmic contractions through binding and the resultant antagonism of the dopamine D1 receptor. Thus, it induces a rapid and sustained tetanic uterotonic effect which shortens the third stage of labor and reduces blood loss. A homolog of ERGONOVINE containing one more CH2 group. (Merck Index, 11th ed) See also: Methylergonovine Maleate (has salt form); Methylergonovine tartrate (is active moiety of). Drug Indication For the prevention and control of excessive bleeding following vaginal childbirth Mechanism of Action Methylergometrine acts directly on the smooth muscle of the uterus and increases the tone, rate, and amplitude of rhythmic contractions through binding and the resultant antagonism of the dopamine D1 receptor. Thus, it induces a rapid and sustained tetanic uterotonic effect which shortens the third stage of labor and reduces blood loss. Methylergonovine acts directly on the smooth muscle of the uterus and increases the tone, rate, and amplitude of rhythmic contractions. Thus, it induces a rapid and sustained tetanic uterotonic effect which shortens the third stage of labor and reduces blood loss. Ergonovine maleate and methylergonovine maleate are pharmacologically similar. Both drugs directly stimulate contractions of uterine and vascular smooth muscle. Following administration of usual therapeutic doses of ergonovine or methylergonovine, intense contractions of the uterus are produced and are usually followed by periods of relaxation. Larger doses of the drugs, however, produce sustained, forceful contractions followed by only short or no periods of relaxation. The drugs increase the amplitude and frequency of uterine contractions and uterine tone which in turn impede uterine blood flow. Ergonovine and methylergonovine also increase contractions of the cervix. Ergonovine and methylergonovine produce vasoconstriction, mainly of capacitance vessels; increased central venous pressure, elevated blood pressure, and, rarely, peripheral ischemia and gangrene may result. Methylergonovine reportedly may interfere with prolactin secretion, but this effect has not been definitely established. Ergot alkaloids are antagonists of actions of 5-hydroxytryptamine and of certain metabolic actions of catecholamines. /Ergot alkaloids/ Therapeutic Uses Oxytocics For routine management after delivery of the placenta; postpartum atony and hemorrhage; subinvolution. Under full obstetric supervision, it may be given in the second stage of labor following delivery of the anterior shoulder. /Included in US product label/ Methylergonovine is a first-line agent for the treatment of postpartum hemorrhage; methylergonovine usually is given after oxytocin. Administration of parenteral ergot alkaloids during the third stage of labor decreases mean blood loss and the incidence of postpartum blood loss of 500 mL or more. /NOT included in US product label/ Ergonovine and methylergonovine should not be used for the induction or augmentation of labor. For more Therapeutic Uses (Complete) data for METHYLERGONOVINE (6 total), please visit the HSDB record page. Drug Warnings /Contraindications of methylergonovine therapy include:/ hypertension; toxemia; pregnancy; and hypersensitivity. Use of Methergine is contraindicated during pregnancy because of its uterotonic effects. This drug should not be administered iv routinely because of the possibility of inducing sudden hypertensive and cerebrovascular accidents. If iv administration is considered essential as a lifesaving measure, methylergonovine should be given slowly over a period of no less than 60 seconds with careful monitoring of blood pressure. Intra-arterial or periarterial injection should be strictly avoided. Caution should be exercised in the presence of sepsis, obliterative vascular disease, hepatic or renal involvement. Also use with caution during the second stage of labor. The necessity for manual removal of a retained placenta should occur only rarely with proper technique and adequate allowance of time for its spontaneous separation. For more Drug Warnings (Complete) data for METHYLERGONOVINE (13 total), please visit the HSDB record page. Pharmacodynamics Methylergometrine is a semisynthetic ergot alkaloid and a derivative of ergonovine and is used for the prevention and control of postpartum and post-abortion hemorrhage. In general, the effects of all the ergot alkaloids appear to results from their actions as partial agonists or antagonists at adrenergic, dopaminergic, and tryptaminergic receptors. The spectrum of effects depends on the agent, dosage, species, tissue, and experimental or physiological conditions. All of the alkaloids of ergot significantly increase the motor activity of the uterus. After small doses contractions are increased in force or frequency, or both, but are followed by a normal degree of relaxation. As the dose is increased, contractions become more forceful and prolonged, resting tonus is markedly increased, and sustained contracture can result. |
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 | 2.9461 mL | 14.7306 mL | 29.4612 mL | |
| 5 mM | 0.5892 mL | 2.9461 mL | 5.8922 mL | |
| 10 mM | 0.2946 mL | 1.4731 mL | 2.9461 mL |