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| Targets |
(R)-MK-5046 itself is the inactive isomer and has no significant biological activity at the Bombesin receptor subtype-3 (BRS-3). The active S-enantiomer, MK-5046, targets BRS-3 (also known as BB3), a G protein-coupled receptor (GPCR) that is a member of the bombesin-like peptide receptor family. BRS-3 is involved in the regulation of energy homeostasis, food intake, body weight, and glucose metabolism. MK-5046 is a specific, orally active, allosteric agonist of BRS-3. (R)-MK-5046 is used as an experimental control.
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| ln Vitro |
In vitro, (R)-MK-5046 is the inactive isomer of MK-5046. While MK-5046 (active S-enantiomer) potently activates human BRS-3 with an IC50 of 27 nM and an EC50 of 25 nM, (R)-MK-5046 has minimal or no activity at the receptor. It serves as an essential negative control in cellular assays to confirm that the observed effects (e.g., calcium mobilization, downstream signaling) are specifically mediated by BRS-3 activation and not due to off-target effects. The compound is the isomer of MK-5046.
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| ln Vivo |
As the inactive isomer, (R)-MK-5046 has no relevant in vivo activity in standard pharmacological models. The active enantiomer, MK-5046, has been studied in animal models of obesity. In diet-induced obese (DIO) mice, MK-5046 (10-30 mg/kg, p.o.) reduces food intake and body weight gain. MK-5046 also improves glucose tolerance and insulin sensitivity. (R)-MK-5046 is used as an inactive control in such studies to confirm that the anti-obesity effects are mediated by BRS-3 agonism. The compound is the isomer of MK-5046 and can be used as an experimental control.
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| Enzyme Assay |
A standard non-cellular binding assay for BRS-3 agonists is a radioligand binding assay using 125I-labeled BRS-3 agonist (e.g., 125I-[D-Tyr6, beta-Ala11, Phe13, Nle14] bombesin (6-14)) and membranes prepared from CHO-K1 cells overexpressing human BRS-3. Membranes are incubated with the radioligand and varying concentrations of the test compound (active MK-5046 or (R)-MK-5046). Bound radioligand is separated by filtration, and radioactivity is counted. The half-maximal inhibitory concentration (IC50) is calculated. (R)-MK-5046 is expected to have no significant inhibition. A functional assay for BRS-3 agonism is a calcium mobilization assay using cells loaded with a calcium-sensitive dye (e.g., Fluo-4).
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| Cell Assay |
A standard functional cellular assay for BRS-3 agonism is a calcium mobilization assay. CHO-K1 cells stably expressing human BRS-3 are loaded with a fluorescent calcium indicator dye (e.g., Fluo-4). The cells are treated with varying concentrations of the test compound (active MK-5046 or (R)-MK-5046). The change in fluorescence is measured by a fluorometric imaging plate reader (FLIPR). The half-maximal effective concentration (EC50) is calculated. Active MK-5046 has EC50 of 25 nM for hBRS-3. (R)-MK-5046 is expected to have no significant calcium flux and serves as an inactive control. (R)-MK-5046 is the isomer of MK-5046 and can be used as an experimental control.
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| Animal Protocol |
In an in vivo study of obesity, diet-induced obese (DIO) mice are divided into groups and treated with vehicle control, (R)-MK-5046 (inactive control), and active MK-5046. Both test compounds are administered orally at doses of 10-30 mg/kg. Food intake is measured daily, and body weight is measured weekly over a 2-4 week period. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) are performed. The active compound is expected to reduce food intake, body weight gain, and improve glucose metabolism, while (R)-MK-5046 should have no effect, serving as a negative control to confirm that the observed effects are due to stereoselective activation of BRS-3 by the S-enantiomer.
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| ADME/Pharmacokinetics |
(R)-MK-5046 has a molecular weight of 444.37 and a molecular formula of C20H18F6N4O. It is a light yellow to yellow solid powder. It is soluble in DMSO and other organic solvents. For in vivo use, it can be formulated in vehicles such as 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline, or 10% DMSO, 90% corn oil, to achieve a clear solution. The active S-enantiomer, MK-5046, is reported to be orally active with good bioavailability. The pharmacokinetic properties of the (R)-isomer are expected to be similar, but with no efficacy. The compound is stable as a powder at -20degC for up to 3 years and at 4degC for 2 years.
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| Toxicity/Toxicokinetics |
As the inactive isomer of MK-5046, (R)-MK-5046 is expected to have lower toxicity than the active BRS-3 agonist. The active S-enantiomer, MK-5046, has been studied in preclinical toxicity studies and found to be tolerable at therapeutic doses. Since (R)-MK-5046 does not activate BRS-3, it is unlikely to produce the on-target effects associated with the active compound, such as reduced food intake and weight loss. Standard safety precautions for handling small molecules should be followed, including the use of personal protective equipment (gloves, lab coat, safety goggles) and working in a well-ventilated area.
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| References |
[1]. Guan XM, et al. Antiobesity effect of MK-5046, a novel bombesin receptor subtype-3 agonist. J Pharmacol Exp Ther. 2011 Feb;336(2):356-364.
[2]. Sebhat IK, et al. Discovery of MK-5046, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity. ACS Med Chem Lett. 2010 Oct 18;2(1):43-47. [3]. Ramos-Alvarez I, et al. The Nonpeptide Agonist MK-5046 Functions As an Allosteric Agonist for the Bombesin Receptor Subtype-3. J Pharmacol Exp Ther. 2022 Aug;382(2):66-78. |
| Additional Infomation |
(R)-MK-5046 (CAS 1021736-25-3) is the inactive R-enantiomer of the potent, selective, and orally active BRS-3 agonist MK-5046. MK-5046, a pyridodiazepine-based compound, was developed by Merck & Co. as a potential anti-obesity agent. It functions as a positive allosteric modulator (PAM) of BRS-3, a receptor involved in the regulation of energy homeostasis. BRS-3 is an orphan GPCR, and MK-5046 was one of the first potent and selective small molecule agonists for this receptor. MK-5046 has been investigated in clinical trials for the treatment of obesity. (R)-MK-5046 is used as an analytical reference standard and a negative control in research. It is strictly for laboratory use and not for human consumption.
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| Molecular Formula |
C20H18F6N4O
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| Molecular Weight |
444.37
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| CAS # |
1021736-25-3
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| Related CAS # |
MK-5046;1022152-70-0
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| Appearance |
Light yellow to yellow solid powder
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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 |
| 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 | 2.2504 mL | 11.2519 mL | 22.5038 mL | |
| 5 mM | 0.4501 mL | 2.2504 mL | 4.5008 mL | |
| 10 mM | 0.2250 mL | 1.1252 mL | 2.2504 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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