Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1

Kholodar, Svetlana A.; Lang, Geoffrey; Cortopassi, Wilian A.; Iizuka, Yoshie; Brah, Harman S.; Jacobson, Matthew P.; England, Pamela M.

doi:10.1021/acschembio.1c00326

Cited by 11 publications

(22 citation statements)

References 35 publications

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“…Interestingly, statins share structural features with known Nurr1 modulators. Fluvastatin and pitavastatin comprise a similar bicyclic nitrogen‐containing scaffold as AQ, [ 3 ] CQ [ 3 ] (Figure 1c ), and analogues [ 15 , 23 ] which is also contained in the Nurr1 binding dopamine metabolite dihydroxyindole [ 13 , 24 ] and indole‐based Nurr1 modulators. [ 25 ] Atorvastatin and rosuvastatin share substructures with certain non‐steroidal anti‐inflammatory drugs (NSAIDs), which were found to bind Nurr1, too.…”

Section: Resultsmentioning

confidence: 99%

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

et al. 2022

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The ligand‐sensing transcription factor Nurr1 emerges as a promising therapeutic target for neurodegenerative pathologies but Nurr1 ligands for functional studies and therapeutic validation are lacking. Here pronounced Nurr1 modulation by statins for which clinically relevant neuroprotective effects are demonstrated, is reported. Several statins directly affect Nurr1 activity in cellular and cell‐free settings with low micromolar to sub‐micromolar potencies. Simvastatin as example exhibits anti‐inflammatory effects in astrocytes, which are abrogated by Nurr1 knockdown. Differential gene expression analysis in native and Nurr1‐silenced cells reveals strong proinflammatory effects of Nurr1 knockdown while simvastatin treatment induces several neuroprotective mechanisms via Nurr1 involving changes in inflammatory, metabolic and cell cycle gene expression. Further in vitro evaluation confirms reduced inflammatory response, improved glucose metabolism, and cell cycle inhibition of simvastatin‐treated neuronal cells. These findings suggest Nurr1 involvement in the well‐documented but mechanistically elusive neuroprotection by statins.

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Section: Resultsmentioning

confidence: 99%

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

et al. 2022

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“…ADME profiling of 4CI, 5CI, and 5CMI predicted them to be non-carcinogenic to mice, to have minimal acute fish toxicities, and not to violate Lipinski’s rule of five ( Supplementary Table S6 ). 5-Chloroindole has also been reported to be non-cytotoxic to the MN9D mouse dopaminergic neuronal cell line ( Kholodar et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Antibiofilm and Antimicrobial Activities of Chloroindoles Against Uropathogenic Escherichia coli

Boya

Lee

2022

Front. Microbiol.

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Uropathogenic Escherichia coli (UPEC) is a nosocomial pathogen associated with urinary tract infections and expresses several virulence factors that cause recurring infections and cystitis of the bladder, which can lead to pyelonephritis. UPEC uses different types of extracellular appendages like fimbriae and pili that aid colonization and adherence to bladder epithelium and can form persistent biofilm-like bacterial communities that aid its survival after the deployment of host immune responses. We investigated the antibiofilm, antimicrobial, and antivirulence properties of three indole derivatives namely, 4-chloroindole, 5-chloroindole, and 5-chloro 2-methyl indole. All the three chloroindoles had MICs of 75 μg/ml and inhibited biofilm formation by an average of 67% at 20 μg/ml. In addition, they inhibited swarming and swimming motilities, which are essential for dissemination from bacterial communities and colonization, reduced cell surface hydrophobicity, and inhibited indole production and curli formation. Gene expression analysis showed all three chloroindoles significantly downregulated the expressions of virulence genes associated with adhesion, stress regulation, and toxin production. A 3D-QSAR analysis revealed substitutions at the fourth and fifth positions of the indole moiety favored antimicrobial activity. Furthermore, these chloroindoles potently inhibited biofilm formation in other nosocomial pathogens and polymicrobial consortia.

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“…Encouraged by the rapid discovery of 3 j and 4 as new Nurr1 agonists with a scaffold already differing markedly from AQ/CQ, we used the amide 4 as the seed molecule for library B (Figure 3) to vary the other half of the molecule and replace the chloroquinoline motif. Therein, we again maintained a balance between structurally related motifs and structural diversity to obtain 21 1). To obtain further insights into the importance of the methylamine vs amide linker, we also prepared the secondary amine analogue 5 of 4 e which confirmed the preference for amides as the amine 5 was less active than the amide 4 e. Table 1.…”

Section: Resultsmentioning

confidence: 99%

Scaffold Hopping from Amodiaquine to Novel Nurr1 Agonist Chemotypes via Microscale Analogue Libraries

et al. 2022

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Several lines of evidence suggest the ligand-sensing transcription factor Nurr1 as a promising target to treat neurodegenerative diseases. Nurr1 modulators to validate and exploit this therapeutic potential are rare, however. To identify novel Nurr1 agonist chemotypes, we have employed the Nurr1 activator amodiaquine as template for microscale analogue library synthesis. The first set of analogues was based on the 7chloroquiolin-4-amine core fragment of amodiaquine and revealed superior N-substituents compared to diethylaminomethylphenol contained in the template. A second library of analogues was subsequently prepared to replace the chloroquinolineamine scaffold. The two sets of analogues enabled a full scaffold hop from amodiaquine to a novel Nurr1 agonist sharing no structural features with the lead but comprising superior potency on Nurr1. Additionally, pharmacophore modeling based on the entire set of active and inactive analogues suggested key features for Nurr1 agonists.

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Analogs of the Dopamine Metabolite 5,6-Dihydroxyindole Bind Directly to and Activate the Nuclear Receptor Nurr1

Cited by 11 publications

References 35 publications

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

Nurr1 Modulation Mediates Neuroprotective Effects of Statins

Antibiofilm and Antimicrobial Activities of Chloroindoles Against Uropathogenic Escherichia coli

Scaffold Hopping from Amodiaquine to Novel Nurr1 Agonist Chemotypes via Microscale Analogue Libraries

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