AI Article Synopsis
- Nurr1 (NR4A2) is a crucial transcription factor in the central nervous system that plays protective and anti-inflammatory roles, making it a target in treating neurodegenerative diseases like Parkinson's and Alzheimer's.
- Current research has focused on developing Nurr1 agonists, but there is a gap in creating inverse agonists that inhibit its activity.
- This study details the structure-activity relationship of oxaprozin, identifying its potential as a moderate inverse Nurr1 agonist and RXR agonist, paving the way for future development of more selective and effective Nurr1 inverse agonists.
Article Abstract
Nuclear receptor related 1 (Nurr1, NR4A2) is a ligand-sensing transcription factor with neuroprotective and anti-inflammatory roles widely distributed in the CNS. Pharmacological Nurr1 modulation is considered a promising experimental strategy in Parkinson's and Alzheimer's disease but target validation is incomplete. While significant progress has been made in Nurr1 agonist development, inverse agonists blocking the receptor's constitutive activity are lacking. Here we report comprehensive structure-activity relationship elucidation of oxaprozin which acts as moderately potent and nonselective inverse Nurr1 agonist and RXR agonist. We identified structural determinants selectively driving RXR agonism or inverse Nurr1 agonism of the scaffold enabling the development of selective inverse Nurr1 agonists with enhanced potency and strong efficacy.
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| http://dx.doi.org/10.1021/acs.jmedchem.4c01218 | DOI Listing |
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