A Nurr1 Agonist Derived from the Natural Ligand DHI Induces Neuroprotective Gene Expression
Markus Egner, Romy Busch, Úrsula López-García, Max Lewandowski, Georg Höfner, Thomas Wein, Julian A. Marschner, Daniel Merk
Abstract
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 ( K d 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.