ArticleiScience2024
Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity.
Article in iScience, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
What it found
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
7 citing papers in PubMed.
- Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload.Nature communications · 2026Article
- NMDA Receptor Mediated Mechanisms in the Post-Stroke Brain: From Physiology to Pathology.Biomolecules · 2026Review
- Potent Anthranilic Anilide-Based TRPM4 Channel Inhibitors Identified by a Structure-Activity Relationship Study.Journal of medicinal chemistry · 2026Article
- Structural mechanism of Necrocide 1 activation of human TRPM4 that triggers necrosis by sodium overload.bioRxiv : the preprint server for biology · 2026Article
- Molecular Mechanisms and Targeted Intervention Strategies of Calcium Overload in Ischemic Stroke.International journal of molecular sciences · 2026Review
- Sub-threshold depolarization differentially regulated by multiple ion channels plays a key role in initiation of baroreflex afferent neurotransmission evidenced from baroreceptor terminals to its cell bodies.Frontiers of medicine · 2025Article
- The TRP channels serving as chemical-to-electrical signal converter.Physiological reviews · 2025Review
Corrections and comments
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.