| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
MLS6357 targets the D3 dopamine receptor (D3R) as a selective positive allosteric modulator (PAM)-antagonist. It exhibits antagonist activity at D3R with no detectable activity against other dopamine receptor subtypes including D1R, D2R, D4R, and D5R (IC50 > 100 microM). MLS6357 does not compete for the orthosteric binding site, as demonstrated by radioligand competition binding assays using [3H]-methylspiperone, confirming its allosteric mechanism of action. The compound displays very limited cross-reactivity with other GPCRs in broad panel screening.
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| ln Vitro |
MLS6357 completely antagonized EC80 concentration of Dopamine-induced cAMP accumulation attenuation (IC50 = 4.5 μM) and D3R-stimulated ERK1/2 phosphorylation (pERK) attenuation (IC50 = 5.6 μM) in HEK293 cells[1]. MLS6357 showed good microsomal stability in human liver microsomes (CLint = 51 μL/min/mg; t1/2 = 13.6 min)[1].
MLS6357 exhibits antagonist activity in D3R-mediated beta-arrestin recruitment assays with IC50 values of 13 +/- 0.9 microM and 14 +/- 1.6 microM. In D3R-mediated Go-BRET assays measuring G-protein activation, MLS6357 shows antagonist activity with an IC50 of 17 +/- 3.0 microM. The compound fully antagonizes dopamine (EC80)-induced attenuation of cAMP accumulation in HEK293 cells with an IC50 of 4.5 microM. MLS6357 also antagonizes D3R-stimulated ERK1/2 phosphorylation (pERK) with an IC50 of 5.6 +/- 1.6 microM. No agonist efficacy was observed at any GPCR in a panel of 168 unique GPCRs. |
| ln Vivo |
MLS6357 has been characterized in vivo through pharmacokinetic studies in mice. While the parent compound's in vivo data are limited, optimized analogues 6a and 10aa demonstrated favorable pharmacokinetics in mice and were found to be brain penetrant. These analogues achieved sufficient concentrations to occupy D3R in vivo following intraperitoneal administration. The compound and its analogues are being investigated as potential therapeutic leads for neuropsychiatric disorders including substance use disorder.
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| Enzyme Assay |
MLS6357 was identified through high-throughput screening of a small molecule library using a D3R-mediated beta-arrestin recruitment assay in 384-well format. Hit compounds were characterized using 7-point concentration-response assays of beta-arrestin recruitment to D3R and D2R. Radioligand competition binding assays using [3H]-methylspiperone in full concentration-response format were performed to verify that MLS6357 does not compete for the orthosteric binding site. Selectivity was assessed using beta-arrestin recruitment to the unrelated prostaglandin E receptor 2 (PTGER2). The compound was also screened against a panel of 168 GPCRs to evaluate off-target activity.
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| Cell Assay |
MLS6357 was evaluated in HEK293 cells expressing D3R using several functional assays. BRET-based beta-arrestin recruitment assays measured antagonist activity with IC50 values of 13 and 14 microM. Go-BRET assays assessing D3R coupling to Go inhibitory protein showed antagonist activity with an IC50 of 17 microM. cAMP accumulation assays measured the compound's ability to antagonize dopamine-induced attenuation of cAMP with an IC50 of 4.5 microM. ERK1/2 phosphorylation (pERK) assays using antibody capture showed antagonist activity with an IC50 of 5.6 microM. All assays were carried out with N = 3 unless otherwise noted.
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| Animal Protocol |
In vivo pharmacokinetic studies were conducted in mice via intraperitoneal (i.p.) administration. Microsome stability was assessed in human, mouse, and rat liver microsomes, with MLS6357 showing intrinsic clearance of 51 microL/min/mg and half-life of 13.6 min in human microsomes. Kinetic solubility was determined to be >100 microM. PAMPA permeability was measured at 3.9 × 10-⁴ cm/sec. Brain penetrance was confirmed for optimized analogues, which achieved sufficient concentrations to occupy D3R in vivo.
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| ADME/Pharmacokinetics |
MLS6357 demonstrates favorable microsome stability in human liver microsomes with an intrinsic clearance of 51 microL/min/mg and a half-life of 13.6 minutes. The compound exhibits high kinetic solubility (>100 microM) and good PAMPA permeability (3.9 × 10-⁴ cm/sec), suggesting favorable absorption properties. Optimized analogues 6a and 10aa showed improved pharmacokinetic profiles and brain penetrance in mice. These properties suggest that MLS6357 and its analogues may serve as viable research tools and therapeutic leads for central nervous system applications.
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| Toxicity/Toxicokinetics |
Detailed toxicology data for MLS6357 are limited in the published literature. Safety data sheets indicate that the compound is harmful if swallowed and very toxic to aquatic life with long-lasting effects. Standard precautionary measures include washing skin thoroughly after handling and avoiding eating, drinking, or smoking when using the product. As a research compound currently in preclinical development, comprehensive toxicological profiling including genotoxicity, carcinogenicity, and repeated-dose toxicity studies have not been reported. Further safety characterization would be required for therapeutic development.
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| References | |
| Additional Infomation |
MLS6357 was discovered through a high-throughput screen of the NIH Molecular Libraries Program 400,000+ small molecule library. Iterative medicinal chemistry was used to synthesize and characterize 137 analogues, with several demonstrating both high D3R selectivity and improved potency. Two promising analogues, 6a and 10aa, showed 10-fold or greater improvements in potency and recapitulated the allosteric PAM-antagonism and D3R selectivity of MLS6357. Schild-type functional assays confirmed MLS6357 acts as a purely non-competitive negative allosteric modulator (NAM) of D3R. The compound is not approved for clinical use and is intended for research purposes only. It is being investigated as a pharmacological probe and potential therapeutic lead for D3R-related pathophysiology, particularly substance use disorder and schizophrenia.
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| Molecular Formula |
C18H22CLN3O3S
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| Molecular Weight |
395.90
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| CAS # |
932544-59-7
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| Appearance |
Typically exists as solids at room temperature
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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 | 2.5259 mL | 12.6295 mL | 25.2589 mL | |
| 5 mM | 0.5052 mL | 2.5259 mL | 5.0518 mL | |
| 10 mM | 0.2526 mL | 1.2629 mL | 2.5259 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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