Publications by authors named "Timothy R Hodges"
Article Synopsis
- The sigma 2 receptor (σR), also known as transmembrane protein 97 (TMEM97), is linked to neuroprotection and may influence neurodegenerative diseases.
- Research on TMEM97 mice revealed that their retinal ganglion cells (RGCs) show resistance to degeneration during ischemic conditions, highlighting the protective role of σR/TMEM97.
- The study supports the potential for developing new neuroprotective treatments for RGC diseases by targeting and inhibiting σR/TMEM97 to prevent cell death.
Article Synopsis
- Huntington's disease (HD) is caused by a genetic mutation leading to neuronal degeneration and currently lacks effective treatment options.
- Small molecules that bind to σR/TMEM97 have been previously shown to offer neuroprotection in various neurodegenerative diseases.
- Recent findings indicate that specific σR/TMEM97-selective compounds can significantly reduce neuronal toxicity caused by the mutant huntingtin protein in HD models, suggesting a potential new therapeutic avenue for treating HD.
Article Synopsis
- This study presents methods for creating 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates using dirhodium tetracarboxylate-catalyzed asymmetric cyclopropanation.
- The reactions are noted for their high diastereoselectivity and the achievement of significant asymmetric induction through chiral auxiliaries or catalysts.
- Various heterocycles, including pyridines and indoles, can participate in the optimized cyclopropanation reactions, with specific catalysts recommended for different substrate types.
Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 ( K = 5.
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- SOS1 is a key protein that helps activate RAS, which plays a vital role in various cellular functions, and its improper activation is linked to about 30% of human cancers, making SOS1 a potential target for cancer treatment.
- Researchers developed a new group of benzimidazole-derived compounds that act as SOS1 agonists, enhancing the exchange of GDP for GTP on RAS even at very low concentrations.
- These compounds not only bind effectively to SOS1 but also significantly increase RAS-GTP levels in cells and result in complex changes in signaling pathways, positioning them as the most potent SOS1 agonists documented so far.
Article Synopsis
- Deregulated RAS activity, often due to mutations, is involved in around 30% of human cancers, but effective treatments for RAS-driven tumors are currently lacking.
- A promising strategy involves targeting proteins interacting with RAS, like the guanine nucleotide exchange factor (GEF) SOS1, to modulate RAS activity.
- Research on an indole series of compounds showed that some can effectively activate the nucleotide exchange process and alter signaling in cancer cells, leading to decreased levels of active RAS-GTP and signaling changes in the MAPK-ERK pathway.
Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol.
View Article and Find Full Text PDFThe nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons.
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- Some norbenzomorphans have a strong attraction to sigma 1 and sigma 2 receptors, and changing substituents on their aromatic ring can affect which receptor subtype they prefer.
- Compounds with different substituents at C7 tend to favor the sigma 1 receptor, while those at C8 are more likely to bind to the sigma 2 receptor.
- This variability in binding suggests that the norbenzomorphan structure could be a valuable tool for creating small molecules that help researchers study the specific effects of targeting these sigma receptors, especially since the sigma 2 receptor's structure is not well understood yet.
Article Synopsis
- A novel method was developed to synthesize gliocladin C and related alkaloids, utilizing a unique nucleophilic addition followed by Friedel-Crafts alkylation to create a key quaternary center.
- This process involved chemoselective reduction and cyclization to achieve a crucial hexahydropyrrolo[2,3-b]indole diketopiperazine intermediate.
- The strategy resulted in the most efficient synthesis of (±)-gliocladin C, (±)-T988C, and (±)-gliocladine C reported to date.
Article Synopsis
- A new structural class of compounds with strong affinity for the sigma 2 receptor has been found, showing promising subtype selectivity compared to the sigma 1 receptor.
- Preliminary data highlights that certain derivatives, like SAS-1121, demonstrate significant selectivity, with SAS-1121 being 574 times more selective for sigma 2.
- Given the sigma 2 receptor's potential links to various health issues and the drug-like properties of these compounds, norbenzomorphan analogues might be valuable for future drug development.