Uses
ML417 is a selective and brain penetrant D3 dopamine receptor (D3R) agonist, with an EC50 of 38 nM. ML417 potently promotes D3R-mediated β-arrestin translocation, G protein mediated signaling, and pERK phosphorylation with minimal effects on other GPCR-mediated signaling. ML417 exhibits neuroprotection against toxin-induced neurodegeneration of dopaminergic neurons[1].
Biological Activity
ML417 is a blood-brain barrier permeable, potent and highly selective agonist of D3 dopamine receptor (D3R) with very limited cross-reactivity at other GPCRs. ML417 potently induces G-protein activation, D3R-mediated b-arrestin translocation and pERK phosphorylation. It does not activate other dopamine receptors. ML417 protect D3R-expressing dopaminergic neurons from 6-OHDA induced cell death.
in 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. ML417 displays a plasma Tmax of 0.5 hours and Cmax of 6500 ng/ml, and a brain Tmax of 0.25 hours and Cmax of 28000 ng/ml[1].
| Animal Model: | 6-8 week old male C57BL/6 mice[1] |
| Dosage: | 20 mg/kg |
| Administration: | I.p. (Pharmacokinetic Analysis) |
| Result: | Brain penetrant and exhibits a plasma half-life of 3.44 hours and a brain half-life of 4.23 hours. Displayed a plasma Tmax of 0.5 hours and Cmax of 6500 ng/ml, and a brain Tmax of 0.25 hours and Cmax of 28000 ng/ml.
|
IC 50
D
3 Receptor: 38 nM (EC
50)
References
[1] Moritz AE, et al. Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist. J Med Chem. 2020;63(10):5526‐5567. DOI:
10.1021/acs.jmedchem.0c00424
