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Purity: ≥98%
ML218 (CID-45115620; ML-218; CID45115620) is a novel, potent and selective T-Type Ca(2+) (Ca(v)3.1, Ca(v)3.2, Ca(v)3.3) inhibitor (Ca(v)3.2, IC(50) = 150 nM in Ca(2+) flux; Ca(v)3.2 IC(50) = 310 nM and Ca(v)3.3 IC(50) = 270 nM, respectively in patch clamp electrophysiology) with good DMPK properties, it displayed acceptable in vivo rat PK and excellent brain levels. Electrophysiology studies in subthalamic nucleus (STN) neurons demonstrated robust effects of ML218 on the inhibition of T-Type calcium current, inhibition of low threshold spike and rebound burst activity. Based on the basal ganglia circuitry in Parkinson's disease (PD), the effects of ML218 in STN neurons suggest a therapeutic role for T-type Ca(2+) channel inhibitors, and ML218 was found to be orally efficacious in haloperidol-induced catalepsy, a preclinical PD model, with comparable efficacy to an A(2A) antagonist, a clinically validated PD target. ML218 proves to be a powerful new probe to study T-Type Ca(2+) function in vitro and in vivo, and freely available.
| Targets |
ML218 demonstrated good free fractions in both rats and humans in plasma protein binding experiments (equilibrium dialysis). ML218 is highly cleared in rats (CLint = 115 mL/min/kg) according to investigations on intrinsic clearance in liver microsomes, whereas it is only weakly to moderately cleared in human liver microsomes (CLint = 12.7 mL/min/kg)[1].
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| ln Vitro |
ML218 demonstrated good free fractions in both rats and humans in plasma protein binding experiments (equilibrium dialysis). ML218 is highly cleared in rats (CLint = 115 mL/min/kg) according to investigations on intrinsic clearance in liver microsomes, whereas it is only weakly to moderately cleared in human liver microsomes (CLint = 12.7 mL/min/kg)[1].
ML218 selectively inhibits T-type calcium currents in subthalamic nucleus (STN) neurons, with approximately 45% inhibition at 3 µM in voltage clamp experiments. In current clamp mode, 3 µM ML218 inhibits >50% of low-threshold spike (LTS) amplitude and >60% of rebound burst activity in STN neurons.[1] |
| ln Vivo |
Rats that have been exposed to a 0.75 mg/kg dosage of haloperidol exhibit cataleptic behavior that is reversed by ML218 (0.03-30 mg/kg; oral administration; once; male Sprague-Dawley rats)[1]. Over the whole dose range, the concentrations of ML218 in the free brain and plasma increase in a dose-proportional manner (3 mg/kg: [plasma] = 98 nM, [brain] = 1.66 μM; 10 mg/kg: [plasma] = 282 nM, [brain] = 5.03 μM; 30 mg/kg: 1.2 μM, [brain] = 17.7 μM)[1]. According to noncompartmental pharmacokinetic analysis, the mean residence time (MRT) of ML218 (1 mg/kg, IV) is almost 7 hours, which is in line with its terminal half-life (t1/2 = 7 hours)[1].
ML218 dose-dependently reverses haloperidol-induced catalepsy in rats (a preclinical Parkinson’s disease model) at oral doses of 1, 3, 10, and 30 mg/kg, with efficacy comparable to an A₂ₐ antagonist at 56.6 mg/kg.[1] |
| Enzyme Assay |
A calcium mobilization assay was performed using a FLIPR-based Ca²⁺ flux assay. HEK293 cells expressing CaV3.2 channels were loaded with Fluo-4 AM dye and exposed to test compounds. Fluorescence was measured before and after stimulus addition to determine inhibition of calcium influx.[1]
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| Cell Assay |
Electrophysiological assessment of CaV3.2 and CaV3.3 channels was conducted using the IonWorks Quattro automated patch clamp system. HEK293 cells stably expressing these channels were plated in a 384-well plate, perforated with amphotericin B, and currents were recorded in response to depolarizing steps. Compound effects were calculated as percentage inhibition of inward currents.[1]
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| Animal Protocol |
Animal/Disease Models: Male SD (Sprague-Dawley) rats (275-299 g) induced by haloperidol[1]
Doses: 0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg , 1 mg/kg, 3 mg/kg, 10 mg/kg, 30 mg/kg Route of Administration: Oral administration; once Experimental Results: Reversed cataleptic behavior in rats induced by a 0.75 mg/kg dose of haloperidol. For the haloperidol-induced catalepsy model, rats were administered haloperidol (0.75 mg/kg, i.p.) 60 minutes before vehicle or ML218 (0.1–30 mg/kg, p.o.). Catalepsy was assessed 30 minutes later by measuring the latency to remove forepaws from a horizontal bar (cutoff 30 s).[1] For pharmacokinetic studies, ML218 was administered intravenously (1 mg/kg) or orally (10 mg/kg) to rats, and blood/brain samples were collected at various time points for LC/MS/MS analysis.[1] |
| ADME/Pharmacokinetics |
The plasma protein binding rate of ML218 was 9.1% in rats and 3.3% in humans. Cytochrome P450 enzyme inhibition: 3A4 IC₅₀ >30 µM, 2C9 IC₅₀ >30 µM, 1A2 IC₅₀ = 10.8 µM, 2D6 IC₅₀ = 1.7 µM. The intrinsic clearance rate in rat liver microsomes was 115 mL/min/kg, and the intrinsic clearance rate in human liver microsomes was 12.7 mL/min/kg. In rats, the plasma clearance rate was 56 mL/min/kg, the mean residence time was approximately 7 hours, the terminal half-life was 7 hours, and the brain/plasma AUC ratio was 7.4–16.9. [1]
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| Toxicity/Toxicokinetics |
ML218 was tested at a concentration of 10 µM against 68 G protein-coupled receptors (GPCRs), ion channels, and transporters. The results showed that it significantly bound only to sodium channel sites 2 and σ1 receptors, while it did not exhibit more than 50% inhibition against other targets (including L- and N-type calcium channels, KATP, and HERG) at a concentration of 10 µM. [1]
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| References | |
| Additional Infomation |
3,5-Dichloro-N-[[(1S,5R)-3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hexane-6-yl]methyl]benzamide is an organohalide and carbonyl compound. ML218 is a probe molecule developed through the MLPCN project, free from intellectual property restrictions. It possesses excellent brain penetration and is intended to study the function of T-type calcium channels in central nervous system disorders such as Parkinson's disease, essential tremor, epilepsy, and pain. [1]
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| Molecular Formula |
C19H26CL2N2O
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| Molecular Weight |
369.328543186188
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| Exact Mass |
368.142
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| CAS # |
1346233-68-8
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| Related CAS # |
ML218 hydrochloride;2319922-08-0;ML218-d9
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| PubChem CID |
45115620
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| Appearance |
White to off-white solid powder
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| LogP |
4.9
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
24
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| Complexity |
443
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| Defined Atom Stereocenter Count |
2
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| SMILES |
ClC1C=C(C=C(C=1)C(NCC1[C@@H]2CN(CCC(C)(C)C)C[C@@H]21)=O)Cl
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| InChi Key |
GSJIGYLGKSBYBC-ALOPSCKCSA-N
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| InChi Code |
InChI=1S/C19H26Cl2N2O/c1-19(2,3)4-5-23-10-16-15(17(16)11-23)9-22-18(24)12-6-13(20)8-14(21)7-12/h6-8,15-17H,4-5,9-11H2,1-3H3,(H,22,24)/t15?,16-,17+
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| Chemical Name |
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6.25 mg/mL (16.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7076 mL | 13.5380 mL | 27.0761 mL | |
| 5 mM | 0.5415 mL | 2.7076 mL | 5.4152 mL | |
| 10 mM | 0.2708 mL | 1.3538 mL | 2.7076 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.
Dose–response curves for ML218 (26b).ACS Chem Neurosci.2011 Dec 21;2(12):730-742. |
ML218 inhibits T-type calcium currents in STN neurons.ACS Chem Neurosci.2011 Dec 21;2(12):730-742. |
ML218 inhibits low threshold spike (LTS) in STN neurons.ACS Chem Neurosci.2011 Dec 21;2(12):730-742. |
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