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| Targets |
M5 muscarinic acetylcholine receptor (CHRM5). ML375 is a negative allosteric modulator (NAM) of the M5 receptor. M5 is the least understood of the five muscarinic receptor subtypes and is primarily expressed in the central nervous system. Negative allosteric modulators bind to a site distinct from the orthosteric binding site and reduce receptor activity without competing with the endogenous ligand.
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| ln Vitro |
In multiple species, ML375 has been found to exhibit low predicted hepatic clearance (CLhep; human, 2.3 mL/min/kg, cynomolgus monkey, 14 mL/min/kg, rat, 18 mL/min/kg) and high metabolic stability. Additionally, ML375 has been found to have low hepatic microsomal intrinsic clearance (CLint; human 2.6 mL/min/kg, cyno 20 mL/min/kg, rat 24 mL/min/kg) [1].
In vitro, ML375 demonstrates potent and selective M5 receptor negative allosteric modulation with IC50 values of 300/790 nM against 10 μM NMS-induced Ca²⁺ mobilization. The compound shows selectivity for M5 over other muscarinic receptor subtypes. Its CNS-penetrant properties make it suitable for studying M5 receptor function in the brain. |
| ln Vivo |
Cocaine's relative intensity and reinforcing effects are lessened by ML375 (10–30 mg/kg; i.p.; once) [2]. ML375 demonstrates a low clearance (CLp, 2.5 mL/min/kg) and an extended elimination half-life in non-human primates (IV) T1/2, 80 hours) and male Sprague-Dawley rats (1 mg/kg IV). Male, cynomolgus monkey, T1/2 = 10 hours, CLp = 3.0 mL/min/kg, 1 mg/kg) [1]. Following the administration of a suspension dosage to male SD rats, ML375 exhibited high oral bioavailability (%F, 80), with a maximum plasma concentration (Cmax) of 1.4 μM and a corresponding time to Cmax (Tmax) of 7 hours [1].
In vivo, ML375 is orally active and brain-penetrant. It is used to investigate the role of M5 receptors in CNS function and behavior. As the first M5-selective NAM with CNS penetration, ML375 is a valuable tool for studying the physiological and pathological roles of M5 receptors. Preclinical studies have explored its effects in models of neurological and psychiatric disorders. |
| Enzyme Assay |
Cell-free receptor binding assays for ML375 use membrane preparations from cells expressing recombinant human M5 muscarinic receptors. The compound is incubated with a radiolabeled muscarinic receptor ligand (e.g., [³H]-NMS) at varying concentrations for 60-120 minutes at room temperature. Nonspecific binding is determined in the presence of an excess of unlabeled muscarinic antagonist. Bound and free radioactivity are separated by filtration, and Ki values are calculated from competition curves.
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| Cell Assay |
Cellular functional assays for ML375 use cell lines stably expressing the M5 muscarinic receptor (e.g., CHO-M5 cells). Cells are seeded in 96-well plates and loaded with a calcium-sensitive fluorescent dye (e.g., Fluo-4). Cells are pre-incubated with ML375 at concentrations ranging from 0.01-1000 nM for 10-30 minutes, then stimulated with the muscarinic agonist carbachol or NMS (10 μM). Intracellular calcium mobilization is measured using a fluorescence plate reader. The negative allosteric modulation is assessed by measuring the reduction in agonist-induced calcium flux. IC50 values are determined from dose-response curves.
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| Animal Protocol |
Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats (70 days old; 260-300 g) injected with cocaine [2]
Doses: 10 mg/kg, 30 mg/kg Route of Administration: intraperitoneal (ip) injection; primary outcome: cocaine self-administration Produces dose-related reductions. In vivo efficacy studies are conducted in rodent models of CNS disorders where M5 receptors are implicated. ML375 is administered orally or intraperitoneally at doses typically ranging from 1-30 mg/kg. Behavioral assays such as the open field test, elevated plus maze, or passive avoidance are used to assess CNS effects. Brain penetration is confirmed by measuring compound concentrations in brain tissue homogenates via LC-MS/MS. Pharmacodynamic studies assess the effects of M5 modulation on neurotransmitter levels and receptor occupancy. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies of ML375 demonstrate that the compound is orally active and brain-penetrant. PK parameters such as Cmax, Tmax, AUC, half-life, oral bioavailability, and brain-to-plasma ratio are determined in preclinical species. The compound's favorable PK properties support its use in CNS research. Metabolic stability is assessed using liver microsome or hepatocyte incubation studies.
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| Toxicity/Toxicokinetics |
Toxicological data for ML375 are limited to preclinical research studies. As a CNS-penetrant M5 NAM, potential toxicities may include effects on CNS function, including cognitive, motor, or autonomic effects. Standard toxicology studies would be required for clinical development. At research-grade doses, the compound is handled with standard laboratory safety precautions.
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| References |
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| Additional Infomation |
ML375 is a research compound for studying M5 muscarinic receptor biology and validating M5 as a therapeutic target in CNS disorders. It is the first M5-selective and CNS-penetrant negative allosteric modulator of a muscarinic acetylcholine receptor. The compound is not an approved drug and has not entered clinical trials. It is available from chemical suppliers for research purposes only. Its selectivity and CNS penetration make it a valuable tool for dissecting the role of M5 receptors in brain function and disease.
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| Molecular Formula |
C23H15CLF2N2O2
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| Molecular Weight |
424.83
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| Exact Mass |
424.079
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| CAS # |
1488362-55-5
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| Related CAS # |
1488362-55-5 (S-isomer);1488362-56-6 (R-isomer);
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| PubChem CID |
71598521
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
611.6±55.0 °C at 760 mmHg
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| Flash Point |
323.7±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.699
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| LogP |
2.65
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
30
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| Complexity |
701
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CN([C@]2(N1C(=O)C3=CC=CC=C32)C4=CC=C(C=C4)Cl)C(=O)C5=CC(=C(C=C5)F)F
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| InChi Key |
GXBAKXRLQAPKEE-QHCPKHFHSA-N
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| InChi Code |
InChI=1S/C23H15ClF2N2O2/c24-16-8-6-15(7-9-16)23-18-4-2-1-3-17(18)22(30)28(23)12-11-27(23)21(29)14-5-10-19(25)20(26)13-14/h1-10,13H,11-12H2/t23-/m0/s1
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| Chemical Name |
(9bS)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydroimidazo[2,1-a]isoindol-5-one
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| Synonyms |
ML-375 VU-0483253 ML 375 VU0483253 ML375VU 0483253
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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 | 2.3539 mL | 11.7694 mL | 23.5388 mL | |
| 5 mM | 0.4708 mL | 2.3539 mL | 4.7078 mL | |
| 10 mM | 0.2354 mL | 1.1769 mL | 2.3539 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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