Compound and inactive control can be requested here.
The nuclear NR4A receptors (nerve growth factor IB-like receptor family) are ligand-activated transcription factors with (neuro)protective properties as part of the immediate early response and have emerged as promising therapeutic targets in various pathologies including neurodegeneration. Nurr1 (NR4A2) plays a critical role in the development, function, and maintenance of dopaminergic neurons. Reduced expression of Nurr1 has been observed in both Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients, as well as in corresponding rodent models, suggesting its potential involvement in the pathogenesis and progression of these disorders.
Chemical structures of ME43 and the negative control ME113.
Based on the Nurr1-DHI complex structure, we have identified high-affinity ligands (Kd 0.08–0.12 μM) targeting the DHI binding site of Nurr1. Optimization of this ligand scaffold yielded a potent NR4A agonist ME43, characterized by favorable physicochemical properties, high selectivity, and low toxicity, making it a valuable chemical probe for studying Nurr1 activation via the DHI site. Treatment of neuronal cells with ME43 led to increased expression of Nurr1-regulated neuroprotective genes, including brain-derived neurotrophic factor (BDNF), supporting therapeutic potential of Nurr1 activation in combating neurodegenerative diseases.
Biological activity summary:
| Physical and chemical properties for ME43 | |
| Molecular weight | 321,76 |
| Molecular formula | C18H12ClN3O |
| IUPAC name | 5-Chloro-N-(quinolin-3-yl)-1H-indole-6-carboxamide |
| AlogP | 4.15 |
| PSA | 57.78 |
| No. of chiral centers | 0 |
| No. of rotatable bonds | 3 |
| No. of hydrogen bond acceptors | 3 |
| No. of hydrogen bond donors | 2 |
| Storage | Stable as a solid at room temperature. Store DMSO stock solutions (10 mM) at -20 °C. Use only 1 freeze/thaw cycle per aliquot. DMSO stocks beyond 3-6 months or 2 freeze/thaw cycles should be tested for activity before use |
| Dissolution | Soluble in DMSO up to 10 mM |
| Physical and chemical properties for ME113 | |
| Molecular weight | 335.79 |
| Molecular formula | C19H14ClN3O |
| IUPAC name | 5-Chloro-N-methyl-N-(quinolin-3-yl)-1H-indole-6-carboxamide |
| AlogP | 4.18 |
| PSA | 48.99 |
| No. of chiral centers | 0 |
| No. of rotatable bonds | 4 |
| No. of hydrogen bond acceptors | 3 |
| No. of hydrogen bond donors | 1 |
| Storage | Stable as a solid at room temperature. Store DMSO stock solutions (10 mM) at -20 °C. Use only 1 freeze/thaw cycle per aliquot. DMSO stocks beyond 3-6 months or 2 freeze/thaw cycles should be tested for activity before use |
| Dissolution | Soluble in DMSO up to 10 mM |
SMILES:
ME43: ClC1=C(C(NC2=CC(C=CC=C3)=C3N=C2)=O)C=C(NC=C4)C4=C1
ME113: ClC1=C(C(N(C)C2=CC(C=CC=C3)=C3N=C2)=O)C=C(NC=C4)C4=C1
InChI:
ME43: InChI=1S/C18H12ClN3O/c19-15-8-12-5-6-20-17(12)9-14(15)18(23)22-13-7-11-3-1-2-4-16(11)21-10-13/h1-10,20H,(H,22,23)
ME113: InChI=1S/C19H14ClN3O/c1-23(14-8-12-4-2-3-5-17(12)22-11-14)19(24)15-10-18-13(6-7-21-18)9-16(15)20/h2-11,21H,1H3
InChIKey:
ME43: ZJPUSKBFLQMYJU-UHFFFAOYSA-N
ME113: AUSKEAIAMTVFBX-UHFFFAOYSA-N
Markus Egner, Romy Busch, Úrsula López-García, Max Lewandowski, Georg Höfner, Thomas Wein, Julian A. Marschner, and Daniel Merk. A Nurr1 Agonist Derived from the Natural Ligand DHI Induces Neuroprotective Gene Expression. J. Med. Chem., 2025, 68, 4829–4847.