ACS Chemical Neuroscience最新文献

{"title":"Role of Calcium in the Regulation of Chronic Stress-Induced Progression of Stress Granule Assembly in N2a Cells.","authors":"Debasmita Saha, Saurabh Kumar, Rishikesh Kumar Gupta, Inderjeet Kaur, Saptarshi Majumdar, Ajith Karunarathne, Lopamudra Giri","doi":"10.1021/acschemneuro.5c00588","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00588","url":null,"abstract":"<p><p>The persistence of stress granules (SGs) and subsequent pathological inclusion are implicated in neurodegeneration. Although SGs formed under acute stress have been well investigated, the role of biophysical factors in the formation of persistent and large SGs in the context of such neurodegeneration remains unclear. Especially, it remains challenging to differentiate between calcium (Ca²⁺) and PERK (PKR-like ER kinase)-mediated SG maturation. In this work, we hypothesize that the maturation of SGs under chronic stress primarily occurs due to an interplay between PERK pathway activation and the accumulation of Ca²⁺. To examine this, we first demonstrate that chronic hypoxia induces the formation of large SGs only in the later phase. Next, we demonstrate that there is significant colocalization of Ca²⁺ and G3BP1 (Ras GTPase-activating protein-binding protein 1) within the late-phase SGs by live cell imaging using laser scanning confocal microscopy. Moreover, the specific inhibition of the L-type Ca²⁺ channel and PERK pathway indicates that Ca²⁺ overloading plays a major role in inducing large-sized SGs. Based on this, we further demonstrated that resveratrol treatment effectively suppressed the large SG by inhibiting <i>CAPN-2</i> (calpain-2) and <i>ATF4</i> (activating transcription factor 4). Our study highlights that ionic interactions assume critical importance in controlling SG size distribution under chronic hypoxia, and resveratrol can be a promising strategy for the reduction of large SGs.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145204924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mass Spectrometry Imaging Reveals the Distribution of a GABRG2 Targeting Antisense Oligonucleotide and Its Functional Effect in Rat Brain.","authors":"Laura van der Vloet, Ronny Mohren, Christophe Bouillod, Georges Da Violante, Emre M Isin, Ron M A Heeren, Pierre Barbier Saint Hilaire, Michiel Vandenbosch","doi":"10.1021/acschemneuro.5c00524","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00524","url":null,"abstract":"<p><p>In recent years, the development of antisense oligonucleotides (ASOs) has gained wide interest as therapeutic agents for their potential in treating neurodegenerative diseases. ASOs are chemically modified oligonucleotides that are designed to bind complementary regions of RNA or DNA and, thereby, modulate the expression of the corresponding protein. Here, we present a multiomics approach to investigate the spatial distribution and biological effect of an ASO designed to target the mRNA that translates for γ-aminobutyric acid A receptor γ2 subunit (GABRG2), which is abundantly expressed within the brain. In this study, a rat model was used to develop a multiomics mass spectrometry (imaging) approach to map ASO distribution in brain and kidney, followed by in-depth analysis of the lipidome, proteome, and metabolome. The ASOs' phosphorothioate-modified backbone was visualized using an optimized matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) protocol, which included the introduction of an organic washing step prior to MALDI-MSI acquisition and an optimized acquisition method. On consecutive tissue sections, reactive matrix FMP10 was applied to enable the visualization of neurotransmitters, which revealed significant alterations for multiple neurotransmitters. Lastly, on the same slide, the ASOs' effect on the lipidome and proteome of the brain was further analyzed. Proteins corresponding to synaptic activity and plasticity were mainly affected by the ASO. This spatial omics approach provides insight into the comprehensive molecular landscape of ASO-mediated interventions and their promise as treatments for neurological disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Lippia grata</i> Schauer: Essential Oil and Phytoceutical Thymol Antioxidants and Neuroprotectors with Inhibition of Acetylcholinesterase and Depressive Behaviors in Adult Zebrafish (<i>D. rerio</i>).","authors":"Luiz F Wemmenson G Moura, Maria Rayane C de Oliveira, Gabriela A do Nascimento, João Gabriel L da Silva, Paulo A T Coelho, Lorena S Lima, Sacha Aubrey A R Santos, Keciany A de Oliveira, Solange de O Pinheiro, Francisco Lucas A Batista, Hamilton M Ishiki, Antonio E Vieira-Neto, Erlândia A M Queiroz, Stenio F Félix, Wildson Max B da Silva, Lucas S Frota, Sara Ingrid C G Barbosa, Selene M de Morais, Maria Izabel F Guedes, Henrique D M Coutinho, Renalison Farias-Pereira, Cassia M M da Silva, Ramon da S Raposo, Adriana R Campos, Francisco Ernani A Magalhães","doi":"10.1021/acschemneuro.5c00331","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00331","url":null,"abstract":"<p><p>Depression, a growing mental disorder, affects millions of people globally and faces treatment challenges due to the low efficacy and adverse effects of conventional antidepressants. In this context, medicinal plants such as <i>Lippia grata</i> Schauer, endemic to Brazil and recognized for their therapeutic properties, stand out as promising alternatives for developing more effective and safe treatments. Therefore, this work reports the standardization of the depression model in adult zebrafish (aZF), in addition to evaluating the antidepressant effect of <i>Lippia grata</i> essential oil (EOLg) and the phytoceutical thymol, as well as their potential neuromodulatory mechanisms and <i>in vitro</i> antioxidant and anticholinesterase (AChE) activities. Initially, aZF were treated with fluoxetine (Flx) or EOLg or thymol or vehicle and subjected to Toxicity and Open Field tests. After 1 h of the same treatments, in other aZF groups, the animals were individually immersed in EtOH for 30 min, with the exception of the naïve group. Subsequently, the aZF were subjected to the Zebrafish Tail Immobilization Test, and the antidepressant effect was characterized by an increase in Mobility Time (s), MT. The possible mechanisms of action were investigated through the administration of antagonists of the serotonergic system. The antioxidant capacity and acetylcholinesterase (AChE) inhibitory effect were assessed <i>in vitro</i>, including the determination of IC₅₀ values for the DPPH and ABTS radicals and the AChE enzyme. Furthermore, molecular docking simulations of thymol with 5-HT receptors were investigated. The toxicological results indicated that the samples are safe against aZF. Flx presented an antidepressant effect, but with a sedative effect, while EOLg and thymol exhibited an antidepressant effect, without a sedative effect and via serotonergic systems. <i>In vitro</i> tests showed antioxidant and neuroprotective potential against AChE in the samples analyzed. Furthermore, <i>in silico</i> tests confirmed the affinity of thymol for the 5-HT_1B, 5-HT_2A, 5-HT_2C, and 5-HT_3A receptors. These findings reinforce the importance of <i>Lippia Grata</i> essential oil as a source of the phytoceutical thymol with neuroprotective potential in neurological disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asparagine Deamidation Attenuates Toxicity, Aggregation, and Microglial Responses of Alzheimer's Amyloid-β.","authors":"Maria Sajimon, Christopher J Wheeler, Alejandro R Foley, Ka Chan, Martin N Griffin, Daniel M Dinakarapandian, Abigail Holberton, Jery Joy, Anant K Paravastu, Levi B Wood, Jevgenij A Raskatov","doi":"10.1021/acschemneuro.5c00544","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00544","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a growing global challenge that imposes a tremendous burden on society and economies. Though recently approved anti-amyloid β (Aβ) immunotherapies show effectiveness in clearing amyloid and slowing cognitive decline, the removal of cerebral Aβ can also cause serious adverse events (SAEs). Therefore, decreasing the detrimental effects of Aβ in the brain without promoting SAEs is an unmet need in AD treatment. Here, we show that deamidation of Asparagine 27(N27) in Aβ1-42 can significantly reduce Aβ's neurotoxicity and decrease selective microglial pro-inflammatory cytokine production. We also show that deamidation of N27 produces a pronounced decrease in Aβ's aggregation propensity and decreases soluble oligomer formation, suggesting a potential mechanism for its mitigation of Aβ's detrimental cellular effects. Modulation of these Aβ properties by N27 deamidation represents a proof of concept for a potential strategy to alter the detrimental effects of Aβ that may not require its removal from the brain. Our findings on reducing Aβ's toxic properties by N27 deamidation may provide a basis for future therapeutic interventions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC6 as a Modulator of DNA Repair in Alzheimer's Disease: From Mechanisms to Therapeutic Perspectives.","authors":"Aneesh Mazumder, Prasenjit Mondal, Can Zhang","doi":"10.1021/acschemneuro.5c00723","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00723","url":null,"abstract":"<p><p>Double-strand breaks (DSBs) are the most cytotoxic DNA damages that arise from endogenous processes (oxidative metabolism as well as external stressors); unrepaired DSBs are consistently found in the hippocampus and cortex of Alzheimer's disease (AD) brains and are thought to contribute to neuronal dysfunction and degeneration. A molecular axis involving histone deacetylase 6 (HDAC6) and an E3 ubiquitin ligase ring finger protein 168 (RNF168) is required for ubiquitination of phosphorylated histone variant H2A.X and the subsequent downstream repair pathway. Herein, we propose that disruption of the HDAC6-RNF168-H2A.X axis is a core mechanism underlying defective DSB repairs in AD and discuss the potential of selectively targeting HDAC6 to restore genomic stability in vulnerable neurons.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indolethylamine <i>N</i>-Methyltransferase Deletion Impacts Mouse Behavior without Disrupting Endogenous Psychedelic Tryptamine Production.","authors":"Cassandra J Hatzipantelis, Lindsay P Cameron, Min Liu, Seona D Patel, Hannah N Saeger, Anna M M Vernier, Yara A Khatib, Brandon J Willis, Louise Lanoue, Oliver Fiehn, David E Olson","doi":"10.1021/acschemneuro.5c00384","DOIUrl":"10.1021/acschemneuro.5c00384","url":null,"abstract":"<p><p>Exogenously administered psychedelics produce both rapid and long-lasting effects on neuroplasticity and behavior, but it is currently unclear if endogenously produced psychedelics can elicit similar effects. There have been relatively few studies on the role of endogenous psychedelics in health and disease, perhaps owing to the difficulty in quantifying their levels and manipulating their production. Here, we describe highly sensitive mass spectrometry-based analytical methods for quantifying endogenous psychedelics in mice, and we disclose a genetic mouse model lacking indolethylamine <i>N</i>-methyltransferase (INMT), an enzyme believed to play a critical role in the production of endogenous psychedelics and previously characterized as a thioether <i>S</i>-methyltransferase. We found that INMT knockout (KO) does not produce any major abnormalities in reproduction or growth, but it does impact a range of mouse behaviors across several distinct domains. However, INMT KO did not result in an obvious decrease in endogenous psychedelic levels, suggesting that psychedelics might be produced by alternative biosynthetic pathways in rodents.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Ethanol and Opioid Receptor Antagonists Naltrexone and LY2444296 on the Organization of Cholesterol- and Sphingomyelin-Enriched Plasma Membrane Domains.","authors":"Sho Oasa, Wai H Mak, Adam L Maddox, Carinna Lima, Andras Saftics, Lars Terenius, Tijana Jovanović-Talisman, Vladana Vukojević","doi":"10.1021/acschemneuro.5c00596","DOIUrl":"10.1021/acschemneuro.5c00596","url":null,"abstract":"<p><p>Excessive consumption of alcohol (ethanol (EtOH)) can lead to alcohol use disorder (AUD). While AUD can be managed through behavioral interventions, there is a great need for pharmacological remedies for this condition. To date, only three pharmacotherapeutic treatments for AUD have been approved by both the U.S. Food and Drug Administration and the European Medicines Agency. This is partly due to an incomplete understanding of the intricate molecular mechanisms through which EtOH affects cellular functions. Here, we focus on EtOH effects on nanoscale organization and the lateral dynamics of molecules in the plasma membrane, the primary cellular component that is affected by this compound. In a cell culture model natively expressing opioid receptors, important targets for medications aimed at preventing relapses in AUD, we used methods with single-molecule sensitivity to characterize the lateral organization and dynamics of cholesterol (Chol)- and sphingomyelin (SM)-enriched domains. Our data reveal that EtOH triggered a reorganization of Chol/SM-enriched domains and increased the plasma membrane fluidity. The general opioid receptor antagonist naltrexone (NTX), approved for relapse prevention in AUD, caused reorganization of Chol/SM-enriched domains, while pretreatment with NTX warded off EtOH-induced plasma membrane reorganization. In contrast, the selective kappa-opioid receptor antagonist LY2444296, at concentrations tested, showed a modest effect on Chol/SM-enriched domain organization and did not protect against EtOH-induced changes in plasma membrane organization. While the significance of these findings for AUD treatment remains uncertain at this stage, our study reveals that the action of NTX is not only limited to blocking opioid receptor activity by preventing agonist binding to the orthosteric binding site, but also is protective against short- and long-range EtOH-induced plasma membrane reorganization. By protecting against EtOH-induced changes in the lateral organization and dynamics of lipids in the plasma membrane, NTX may affect physiological outcomes through previously unrecognized noncanonical mechanisms.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Autism-Associated Serotonin Transporters by Palmitoylation: Insights into the Molecular Pathogenesis and Targeted Therapies for Autism Spectrum Disorder.","authors":"Christopher R Brown, James D Foster","doi":"10.1021/acschemneuro.5c00240","DOIUrl":"10.1021/acschemneuro.5c00240","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a developmental disorder of the nervous system characterized by a deficiency in interpersonal communication skills, a pathologic tendency for repetitive behaviors, and highly restrictive interests. The spectrum is a gradient-based construct used to categorize the widely varying degrees of ASD phenotypes, and has been linked to a genetic etiology in 25% of cases. Prior studies have revealed that 30% of ASD patients exhibit hyperserotonemia, or severely elevated whole blood serotonin (5HT), implicating the serotonergic system in the pathogenesis of ASD. Likewise, escitalopram, a selective-serotonin reuptake inhibitor (SSRI), has been demonstrated to effectively improve core ASD symptoms potentially by modulating abnormal brain activation in ASD patients. Molecular studies have uncovered proband patients with rare mutations in the serotonin transporter (SERT) that manifest enhanced surface expression and 5HT transport capacity, suggesting that abnormal enhancement of SERT function may be involved in the pathogenesis of ASD. Here, we reveal that palmitoylation is enhanced in the ASD SERT F465L and L550V coding variants, and confirm prior reports of enhanced kinetic activity and surface expression of F465L. Furthermore, treatment of F465L with the irreversible palmitoyl acyl-transferase inhibitor, 2-bromopalmitate (2BP), or escitalopram, rectified enhanced F465L palmitoylation, surface expression, and transport capacity to basal WT levels. Overall, our results implicate disordered SERT palmitoylation in the pathogenic mechanism of ASD, with basal recovery of these processes following escitalopram treatment providing insight into its molecular utility as an ASD therapeutic.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Glycolysis for Spinal Cord Injury: Regulatory Mechanisms and Therapeutic Prospects.","authors":"Shenghao Qian, Caizhen Shi, Bingbing Wang, Yanjie Guo, Li Dan, Zhuokun Dang, Xinwei Zhao, Feng Gao, Yanling Yang, Juan Shen, Lin Zhao","doi":"10.1021/acschemneuro.5c00604","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00604","url":null,"abstract":"<p><p>Spinal cord injury (SCI) is a severe neurological disorder that not only causes significant physical and psychological harm to patients but also imposes a substantial economic burden on families and society. Following SCI, a cascade of secondary events occurs, including inflammatory responses, scar formation, and mitochondrial dysfunction. Numerous studies have demonstrated that glycolysis plays a crucial role in the pathophysiological changes post-SCI and may serve as a promising therapeutic target for future SCI treatments. This account systematically summarizes the alterations in glycolysis after SCI, focusing on three key aspects: the activation pathways of glycolysis, changes in metabolic rates and metabolites, and the expression levels of related enzymes and molecules. Furthermore, it highlights the mechanisms by which glycolysis-targeted interventions promote SCI repair, including modulation of inflammatory responses, oxidative stress, apoptosis, and axonal regeneration. Additionally, the applications and limitations of glycolysis-targeting drugs and other emerging therapeutic approaches are critically analyzed. Finally, this review outlines preliminary achievements and prospects in the clinical translation of glycolysis-targeted therapies for SCI. This review summarizes the mechanisms underlying the regulation of glycolysis-targeting SCI, along with current major therapeutic strategies and associated challenges, thereby offering potential insights into the treatment of SCI.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145147064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computationally Motivated Discovery of Biogenic Compounds with Potent CDK9 Inhibition and In Vitro Effects against Glioblastoma.","authors":"Zahra R Khan, Philip J Welsby, Izabela Stasik, Joseph M Hayes","doi":"10.1021/acschemneuro.5c00557","DOIUrl":"10.1021/acschemneuro.5c00557","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common malignant brain tumor in adults but with limited and poorly effective treatment protocols. Kinase inhibitors either as a mono- or as a combination therapy have considerable potential as novel treatments for GBM, with cyclin-dependent kinase 9 (CDK9) a promising target. Here, we present a multistep computationally motivated and structure-based approach to the discovery of CDK9 inhibitors. Active/decoy benchmarking calculations considered structural data from available CDK9-ligand crystal structures, including the potential of multiple protein structure docking. Using an optimized virtual screening approach that included 3D pharmacophore prefiltering of compounds and Glide docking calculations, six novel low micromolar inhibitors from the ZINC15 biogenic database were identified, validated as hits using in vitro CDK9/cyclin T1 binding assays. Of these compounds, <b>1</b> (3,5-disubstituted barbiturate-type core scaffold) demonstrated potent low micromolar effects (IC₅₀s ∼8-13 μM at 72 h) on the cell viability of three GBM cell-lines (U87-MG, T98G, and U251-MG) in a time- and concentration-dependent manner, with compound <b>7</b> (a pyrano[2,3-<i>f</i>]chromene-4,8-dione) more effective against patient-derived PD301 cells. The compounds had good predicted oral bioavailability and four of the six inhibitors potential for blood-brain barrier permeability. Given their structural novelty, the identified CDK9 inhibitor scaffolds can be further explored for their potential against CNS conditions, including <b>1</b> and <b>7</b> against GBM.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145135979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}