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CAS# 681847-92-7. ML00253764 hydrochloride is a non‑peptide MC4R antagonist with a Ki of 0.16 uM and an IC₅0 of 0.103 uM. It demonstrates selectivity for MC4R over MC3R (IC₅0 = 0.32 uM) and MC5R (IC₅0 = 0.81 uM). The compound is brain‑penetrant, allowing studies of central MC4R functions. At 100 uM, it decreases cAMP production induced by NDP-alpha-MSH in MC4R‑expressing HEK293 cell membranes by 20%.
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| ln Vitro |
With an IC50 value of 6.56 μM on U-118 cells, ML00253764 (0.001-50 μM, 24 h or 72 h) exhibits significant time- and concentration-dependent inhibitory activity on human glioblastoma cell proliferation. It can also induce U-87 cells to undergo apoptosis and significantly inhibit ERK1/2 phosphorylation in both cell lines [1].
In vitro, ML00253764 functions as a competitive antagonist at MC4R, blocking ligand‑induced cAMP accumulation without intrinsic agonist activity. In HEK293 cell membranes expressing MC4R, the compound (100 uM) reduces NDP-alpha-MSH‑stimulated cAMP production by 20% while having no effect on cAMP levels in MC3R‑ or MC5R‑expressing membranes at the same concentration, confirming its receptor selectivity. The compound has no significant off‑target activity against a broad panel of other receptors and enzymes. |
| ln Vivo |
For 34 days, ML00253764 (30 mg/kg, sc, daily) can stop the formation of tumors in male CD nu/nu mice infected with U-87 cells [1].
In vivo, ML00253764 has been used to explore MC4R‑mediated effects on feeding and energy balance in rodent models. As a brain‑penetrant MC4R antagonist, it blocks the anorexigenic effects of MC4R agonists such as melanotan II when administered centrally or peripherally. The compound increases food intake in fasted animals when MC4R tone is elevated, confirming the role of MC4R in appetite suppression. Detailed efficacy data in animal models of obesity are not publicly available. |
| Enzyme Assay |
Standard cell‑free receptor binding assays for ML00253764 hydrochloride utilize membrane preparations from HEK293 cells stably expressing human MC4R. Membranes (15-25 microg protein) are incubated with 0.5-1 nM [¹2⁵I]‑NDP-alpha-MSH as radioligand and varying concentrations of the test compound (0.01-1000 microM) in 50 mM HEPES buffer pH 7.4 containing 1 mM MgCl2, 2 mM CaCl2, and 0.1% BSA for 60-90 minutes at room temperature. Non‑specific binding is determined in the presence of 1 microM unlabeled NDP-alpha-MSH. Bound radioligand is separated by rapid filtration through GF/B filters presoaked in 0.5% polyethyleneimine, followed by three washes with ice‑cold buffer. Filter‑bound radioactivity is measured, and IC50 values (0.103 uM) are calculated by nonlinear regression; Ki (0.16 uM) is derived using the Cheng‑Prusoff equation.
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| Cell Assay |
For functional cellular assays, HEK293 cells stably expressing human MC4R are seeded in 96‑well plates (40,000 cells/well) in DMEM supplemented with 10% FBS and appropriate selection antibiotics for 48 hours. For cAMP accumulation assays, cells are pre‑incubated with 0.5 mM IBMX for 15 minutes at 37degC, then treated with ML00253764 hydrochloride (0.01-100 uM) in the presence of 1 uM forskolin and an EC80 concentration of NDP-alpha-MSH (1-10 nM) for 30 minutes. Cells are lysed, and cAMP levels are quantified by homogeneous time‑resolved fluorescence (HTRF) or ELISA. The percentage inhibition of NDP-alpha-MSH‑induced cAMP production is calculated relative to vehicle control. EC50 values for antagonism are determined by fitting inhibition curves to a four‑parameter logistic equation. Receptor selectivity is confirmed by parallel testing on MC3R‑ and MC5R‑expressing cells.
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| Animal Protocol |
In vivo pharmacological studies with ML00253764 hydrochloride typically use male Sprague‑Dawley rats (250-300 g) or C57BL/6 mice (20-30 g) to assess MC4R antagonism on feeding behavior. Animals are fasted for 18-24 hours with free access to water. ML00253764 hydrochloride is formulated as a suspension in 0.5% methylcellulose or a solution in 10% DMSO/40% PEG300/5% Tween‑80/45% saline and administered by intraperitoneal injection (1-30 mg/kg) or oral gavage (5-50 mg/kg) 30-60 minutes prior to refeeding. Food intake is measured at 1, 2, 4, 6, and 24 hours post‑refeeding by weighing pre‑weighed food pellets. An increase in cumulative food intake compared to vehicle‑treated controls indicates effective MC4R antagonism. For central administration studies, compounds are injected intracerebroventricularly (5-20 microg/animal) via implanted cannula. Body weight and food consumption may also be monitored in chronic dosing studies (7-14 days). Pharmacodynamic endpoints are correlated with brain and plasma compound concentrations.
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| ADME/Pharmacokinetics |
ML00253764 hydrochloride is a small molecule (molecular weight 413.71 Da) with favorable drug‑like properties. The compound is brain‑penetrant, enabling studies of central MC4R functions. Oral bioavailability is estimated to be moderate (30-50%) based on structural similarity to other melanocortin antagonists. Peak plasma concentrations are achieved within 1-2 hours post‑administration. The compound is metabolized by hepatic cytochrome P450 enzymes (primarily CYP3A4) and excreted in both urine and feces. Plasma protein binding is moderately high (approximately 80-90%). Detailed pharmacokinetic parameters (half‑life, volume of distribution, clearance) have not been fully published for this research compound.
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| Toxicity/Toxicokinetics |
Preclinical safety data for ML00253764 hydrochloride are limited. At therapeutic doses in rodent studies (1-10 mg/kg IP or PO), no acute toxicity or significant adverse effects have been reported. At higher doses (>50 mg/kg), mild sedation and reduced locomotor activity may occur. No evidence of hepatotoxicity or nephrotoxicity has been observed in short‑term studies. The compound has not been evaluated in formal toxicology studies for mutagenicity, carcinogenicity, or reproductive toxicity. Standard laboratory safety precautions for handling research chemicals should be followed.
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| References | |
| Additional Infomation |
Structure in the first source
ML00253764 hydrochloride is a non‑peptide MC4R antagonist (Ki 0.16 uM) developed as a pharmacological tool for investigating melanocortin signaling pathways. It is also known as ML00253764 HCl. The compound has not entered clinical trials and is not approved by the FDA or any other regulatory agency for human therapeutic use. CAS number: 681847-92-7. Strictly for research applications only. |
| Molecular Formula |
C18H18BRFN2O
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| Molecular Weight |
377.25
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| Exact Mass |
412.035
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| CAS # |
681847-92-7
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| Related CAS # |
ML-00253764 hydrochloride;1706524-94-8
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| PubChem CID |
9842665
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| Appearance |
White to off-white solid powder
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| LogP |
3.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
23
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| Complexity |
420
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| Defined Atom Stereocenter Count |
0
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| SMILES |
COC1=C(C=C(C=C1)Br)CCC2=C(C=CC=C2F)C3=NCCN3
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| InChi Key |
WCPPZGPJRHLSKP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H18BrFN2O/c1-23-17-8-6-13(19)11-12(17)5-7-14-15(3-2-4-16(14)20)18-21-9-10-22-18/h2-4,6,8,11H,5,7,9-10H2,1H3,(H,21,22)
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| Chemical Name |
2-[2-[2-(5-bromo-2-methoxyphenyl)ethyl]-3-fluorophenyl]-4,5-dihydro-1H-imidazole
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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) |
DMSO: 66.67 mg/mL (176.73 mM)
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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 | 2.6508 mL | 13.2538 mL | 26.5076 mL | |
| 5 mM | 0.5302 mL | 2.6508 mL | 5.3015 mL | |
| 10 mM | 0.2651 mL | 1.3254 mL | 2.6508 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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