ML417 is a novel and selective agonist of D3 dopamine receptor, it potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. ML417 demonstrated remarkable global selectivity when screened against several G protein-coupled receptors. Its remarkable selectivity may be explained by the unique way that ML417 interacts with the D3R, according to molecular modeling. It was also discovered that ML417 shields dopaminergic neurons produced from iPSCs from neurodegeneration.
Physicochemical Properties
| Molecular Formula | C22H25N3O3 |
| Molecular Weight | 379.45220541954 |
| Exact Mass | 379.19 |
| Elemental Analysis | C, 69.64 H, 6.64 N, 11.07 O, 12.65 |
| CAS # | 1386162-69-1 |
| PubChem CID | 27842480 |
| Appearance | Solid powder |
| LogP | 3.3 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 28 |
| Complexity | 501 |
| Defined Atom Stereocenter Count | 0 |
| InChi Key | HAZPAMUWUHDPDA-UHFFFAOYSA-N |
| InChi Code | InChI=1S/C22H25N3O3/c1-27-18-6-8-19(9-7-18)28-15-14-24-10-12-25(13-11-24)22(26)21-16-17-4-2-3-5-20(17)23-21/h2-9,16,23H,10-15H2,1H3 |
| Chemical Name | 1H-indol-2-yl-[4-[2-(4-methoxyphenoxy)ethyl]piperazin-1-yl]methanone |
| Synonyms | ML417; ML-417; ML 417 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | D3 Receptor ( EC50 = 38 nM ) |
| ln Vitro |
ML417 displays a Ki of 1.24 µM for the D3R. For numerous signaling pathways connected to D3R activation, ML417 is a complete and powerful agonist[1]. ML417 potently inhibits the accumulation of cAMP with an EC50 of 86 nM and an efficacy equivalent to dopamine. ML417 shows submicromolar affinity for just three targets: σ-1, 5-HT2B serotoninergic, and β1-adrenergic receptors. ML417 promotes β-arrestin recruitment to the D3R-WT with an EC50 of 1.4 nM[1]. ML417 (0.005–5 μM; 24 hours) D3R-expressing dopaminergic neurons are shielded from 6-OHDA-induced cell death[1]. |
| ln Vivo | In vivo pharmacokinetics experiments in mice (using 20 mg/kg; i.p.) reveals that ML417 is brain penetrant and exhibits a plasma half-life of 3.44 hours and a brain half-life of 4.23 hours. In vivo pharmacokinetics experiments in mice (using 20 mg/kg; i.p.) reveals that ML417 is brain penetrant and exhibits a plasma half-life of 3.44 hours and a brain half-life of 4.23 hours. ML417 exhibits a brain Tmax of 0.25 hours and a Cmax of 28000 ng/ml, in addition to a plasma Tmax of 0.5 hours and a Cmax of 6500 ng/ml[1]. |
| Animal Protocol |
6-8 week old male C57BL/6 mice 20 mg/kg I.p. (Pharmacokinetic Analysis) |
| References |
[1]. Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist. J Med Chem. 2020;63(10):5526‐5567. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~50 mg/mL (~131.8 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (13.18 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 50.0 mg/mL clear DMSO stock solution to 900 μL of 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 | 2.6354 mL | 13.1770 mL | 26.3539 mL | |
| 5 mM | 0.5271 mL | 2.6354 mL | 5.2708 mL | |
| 10 mM | 0.2635 mL | 1.3177 mL | 2.6354 mL |