A Nurr1 Agonist Derived from the Natural Ligand DHI Induces Neuroprotective Gene Expression

The dopamine metabolite 5,6-dihydroxyindole (DHI) has been discovered as a natural Nurr1 ligand with potential biological relevance and is an attractive lead for Nurr1 modulator development but exhibits chemical reactivity and weak potency. We have systematically explored the SAR of 5-chloroindole-6-carboxamide as a DHI mimetic scaffold and identified the first high-affinity (Kd 0.08–0.12 μM) ligands of the DHI binding site of Nurr1. An optimized Nurr1 agonist of this scaffold endowed with favorable physicochemical properties, high selectivity, and low toxicity emerges as a chemical tool to explore the biological impact of Nurr1 activation via the DHI binding site. Treatment of neuronal cells with this compound mediated enhanced expression of Nurr1-regulated neuroprotective genes like brain-derived neurotrophic factor (BDNF), supporting the great potential of Nurr1 activation in neurodegeneration.