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

  • J Med Chem. 2025 Feb 27;68(4):4829-4847. doi: 10.1021/acs.jmedchem.4c03104.
Markus Egner  1 ,  Romy Busch  1 ,  Úrsula López-García  1 ,  Max Lewandowski  1 ,  Georg Höfner  1 ,  Thomas Wein  1 ,  Julian A Marschner  1 ,  Daniel Merk  1
Affiliations
  • 1. Ludwig-Maximilians-Universität (LMU) München, Department of Pharmacy, 81377 Munich, Germany.
PMID: 39919139 DOI: 10.1021/acs.jmedchem.4c03104
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 (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.

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