ACS Chemical Neuroscience最新文献_第3页

Detecting and Tracking β-Amyloid Oligomeric Forms and Dynamics In Vitro by a High-Sensitivity Fluorescent-Based Assay.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-29 DOI: 10.1021/acschemneuro.4c00312

Yanyan Zhao, Oleksandr Brener, Ewa Andrzejewska, Jiapeng Wei, CloudOuterMan Reiß, Ole Tietz, Tuomas P J Knowles, Franklin I Aigbirhio

{"title":"Detecting and Tracking β-Amyloid Oligomeric Forms and Dynamics In Vitro by a High-Sensitivity Fluorescent-Based Assay.","authors":"Yanyan Zhao, Oleksandr Brener, Ewa Andrzejewska, Jiapeng Wei, CloudOuterMan Reiß, Ole Tietz, Tuomas P J Knowles, Franklin I Aigbirhio","doi":"10.1021/acschemneuro.4c00312","DOIUrl":"10.1021/acschemneuro.4c00312","url":null,"abstract":"Aggregation of β-amyloid protein is a hallmark pathology of the neurodegenerative disorder Alzheimer's disease and proceeds from monomers to insoluble misfolded fibril forms via soluble and highly toxic oligomeric intermediates. Given the dual feature of being the most toxic form of the Aβ aggregate proteome and an early marker of pathogenesis, there is a need for sensitive methods that can be used to detect Aβ oligomers and investigate the dynamics of aggregation. Herein, we describe a method based on the application of an oligomer-sensitive fluorescent chemical probe pTP-TFE combined with the use of a QIAD (Quantitative determination of Interference with Aβ Aggregate Size Distribution) assay to correctly identify Aβ oligomers in high sensitivity. pTP-TFE was evaluated and compared to thioflavin T and pFTAA, the two most widely used amyloid fibril dyes, and shown to be the only probe capable of detecting significant differences across all oligomeric species of β-amyloid. Furthermore, by observing changes in pTP-TFE fluorescence emission over time, we could track the dynamics of oligomer populations and thereby obtain kinetic information on the Aβ42 dynamic aggregation model. Therefore, we have established a highly sensitive, readily available, and simple method for studying β-amyloid protein aggregation dynamics.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4383-4389"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749417","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}

引用次数: 0

From Nutritional Patterns to Behavior: High-Fat Diet Influences on Inhibitory Control, Brain Gene Expression, and Metabolomics in Rats.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-28 DOI: 10.1021/acschemneuro.4c00297

Diego Ruiz-Sobremazas, Ana Cristina Abreu, Ángeles Prados-Pardo, Elena Martín-González, Ana Isabel Tristán, Ignacio Fernández, Margarita Moreno, Santiago Mora

{"title":"From Nutritional Patterns to Behavior: High-Fat Diet Influences on Inhibitory Control, Brain Gene Expression, and Metabolomics in Rats.","authors":"Diego Ruiz-Sobremazas, Ana Cristina Abreu, Ángeles Prados-Pardo, Elena Martín-González, Ana Isabel Tristán, Ignacio Fernández, Margarita Moreno, Santiago Mora","doi":"10.1021/acschemneuro.4c00297","DOIUrl":"10.1021/acschemneuro.4c00297","url":null,"abstract":"Impulsive and compulsive behaviors are associated with inhibitory control deficits. Diet plays a pivotal role in normal development, impacting both physiology and behavior. However, the specific effects of a high-fat diet (HFD) on inhibitory control have not received adequate attention. This study aimed to explore how exposure to a HFD from postnatal day (PND) 33 to PND77 affects impulsive and compulsive behaviors. The experiment involved 40 Wistar rats subjected to HFD or chow diets. Several tasks were employed to assess behavior, including variable delay to signal (VDS), five choice serial reaction time task (5-CSRTT), delay discounting task (DDT), and rodent gambling task (rGT). Genetic analyses were performed on the frontal cortex, and metabolomics and fatty acid profiles were examined by using stool samples collected on PND298. Our results showed that the HFD group exhibited increased motor impulsive behaviors while not affecting cognitive impulsivity. Surprisingly, reduced impulsive decision-making was shown in the HFD group. Furthermore, abnormal brain plasticity and dopamine gene regulation were shown in the frontal cortex, while metabolomics revealed abnormal fatty acid levels.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4369-4382"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749420","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}

引用次数: 0

Visualization of Unconjugated Bilirubin In Vivo with a Novel Approach Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging in a Rat Model.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-30 DOI: 10.1021/acschemneuro.4c00604

Lin Yang, Yan Cheng, Yanlong Jia, Zhen Cao, Zerui Zhuang, Xiaolei Zhang, Jitian Guan, Rongzhi Cai, Yan Lin, Renhua Wu

{"title":"Visualization of Unconjugated Bilirubin In Vivo with a Novel Approach Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging in a Rat Model.","authors":"Lin Yang, Yan Cheng, Yanlong Jia, Zhen Cao, Zerui Zhuang, Xiaolei Zhang, Jitian Guan, Rongzhi Cai, Yan Lin, Renhua Wu","doi":"10.1021/acschemneuro.4c00604","DOIUrl":"10.1021/acschemneuro.4c00604","url":null,"abstract":"Unconjugated bilirubin (UCB) visualization is valuable for early bilirubin encephalopathy (BE) diagnosis and management. UCB neurotoxicity is a challenge, necessitating improved imaging modalities for precise localization and characterization. This study developed a noninvasive method for UCB imaging in the brain using chemical exchange saturation transfer (CEST) magnetic resonance imaging, which visualizes UCB distribution through amide-bulk water proton exchange, a process termed bilirubin CEST (Bil-CEST) imaging. Bil-CEST imaging parameters were initially optimized; the exchange rate of the amide protons of UCB was calculated. Bil-CEST imaging characteristics and specificity were assessed using in vitro images of UCB solutions under different conditions and images of other brain metabolites. Bil-CEST maps of the rat brain were collected at the baseline and dynamically, postinjection of the UCB solution or vehicle into lateral ventricles of Sprague-Dawley rats. The model was validated using a water maze and pathological staining. In vitro, the Bil-CEST effect was observed at approximately 5.5 ppm downfield from bulk water. This effect was proportional to the UCB concentration and B1 amplitude. In vivo, Bil-CEST imaging revealed a progressive enhancement following a lateral ventricular UCB injection. Conversely, no significant imaging changes were observed in the vehicle group. Compared with the vehicle group, the UCB group had more hippocampal neuronal apoptosis and worse cognitive function. These findings highlight the utility of Bil-CEST in direct UCB imaging, indicating its potential as a clinically valuable biomarker for BE diagnosis and management.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4533-4543"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764532","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}

引用次数: 0

Ultrasensitive Detection of Blood-Based Alzheimer's Disease Biomarkers: A Comprehensive SERS-Immunoassay Platform Enhanced by Machine Learning. 超灵敏检测基于血液的阿尔茨海默病生物标记物：通过机器学习增强的综合 SERS 免疫测定平台。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-11-13 DOI: 10.1021/acschemneuro.4c00369

A N Resmi, Shaiju S Nazeer, M E Dhushyandhun, Willi Paul, Binu P Chacko, Ramshekhar N Menon, Ramapurath S Jayasree

{"title":"Ultrasensitive Detection of Blood-Based Alzheimer's Disease Biomarkers: A Comprehensive SERS-Immunoassay Platform Enhanced by Machine Learning.","authors":"A N Resmi, Shaiju S Nazeer, M E Dhushyandhun, Willi Paul, Binu P Chacko, Ramshekhar N Menon, Ramapurath S Jayasree","doi":"10.1021/acschemneuro.4c00369","DOIUrl":"10.1021/acschemneuro.4c00369","url":null,"abstract":"Accurate and early disease detection is crucial for improving patient care, but traditional diagnostic methods often fail to identify diseases in their early stages, leading to delayed treatment outcomes. Early diagnosis using blood derivatives as a source for biomarkers is particularly important for managing Alzheimer's disease (AD). This study introduces a novel approach for the precise and ultrasensitive detection of multiple core AD biomarkers (Aβ40, Aβ42, p-tau, and t-tau) using surface-enhanced Raman spectroscopy (SERS) combined with machine-learning algorithms. Our method employs an antibody-immobilized aluminum SERS substrate, which offers high precision, sensitivity, and accuracy. The platform achieves an impressive detection limit in the attomolar (aM) range and spans a wide dynamic range from aM to micromolar (μM) concentrations. This ultrasensitive and specific SERS immunoassay platform shows promise for identifying mild cognitive impairment (MCI), a potential precursor to AD, from blood plasma. Machine-learning algorithms applied to the spectral data enhance the differentiation of MCI from AD and healthy controls, yielding excellent sensitivity and specificity. Our integrated SERS-machine-learning approach, with its interpretability, advances AD research and underscores the effectiveness of a cost-efficient, easy-to-prepare Al-SERS substrate for clinical AD detection.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4390-4401"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612709","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}

引用次数: 0

Structural Analysis of Variants of the Ferritin Light Chain Protein and Its Relationship with Neuroferritinopathy.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-18 Epub Date: 2024-12-06 DOI: 10.1021/acschemneuro.4c00400

Madelin Gómez Hernández, Alejandro Soto-Ospina, Cristian Andrés Osorio, Andrés Villegas-Lanau

{"title":"Structural Analysis of Variants of the Ferritin Light Chain Protein and Its Relationship with Neuroferritinopathy.","authors":"Madelin Gómez Hernández, Alejandro Soto-Ospina, Cristian Andrés Osorio, Andrés Villegas-Lanau","doi":"10.1021/acschemneuro.4c00400","DOIUrl":"10.1021/acschemneuro.4c00400","url":null,"abstract":"Ferritin is a highly conserved spherical protein that stores iron and possesses triple and quadruple symmetry input ports. Additionally, it is composed of light chains that can be affected by post-translational mutations, reducing the iron storage capacity in the brain and leading to neuroferritinopathy, which is a rare disease with limited bioinformatics data. In this study, we analyzed the biochemical mechanism of different ferritin mutations reported in the literature, through the characterization and determination of the in silico structural model by searching databases, implementing bioinformatics programs such as Jalview, NetNGlyc 1.0, NetOGlyc 3.1, and three-dimensional structure predictors with machine learning such as Alphafold, demonstrating the generation of hairpin and steric hindrances that hinder the aggregation of subunits and changes in the size and arrangement of quadruple and triple entry holes of the A96T mutation compared to the wild-type protein, since in the quadruple entry hole, a decrease in area is observed compared to the wild-type protein and the triple entry hole has a decrease in distance measurements of 6.504 Å. This possibly affects the functionality of the protein, thus releasing high concentrations of iron in the brain and causing neurodegeneration.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"4402-4417"},"PeriodicalIF":4.1,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789412","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}

引用次数: 0

Unraveling Copper Imbalance in Autism Spectrum Disorder: Mechanistic Insights from the Valproic Acid Mouse Model.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-17 DOI: 10.1021/acschemneuro.4c00708

Weibo Ling, Weichao Wang, Dawei Lu, Qian Liu, Guibin Jiang

{"title":"Unraveling Copper Imbalance in Autism Spectrum Disorder: Mechanistic Insights from the Valproic Acid Mouse Model.","authors":"Weibo Ling, Weichao Wang, Dawei Lu, Qian Liu, Guibin Jiang","doi":"10.1021/acschemneuro.4c00708","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00708","url":null,"abstract":"Abnormal copper (Cu) levels are often closely associated with neurological disorders including neurodevelopmental conditions, such as autism spectrum disorder (ASD). However, the mechanisms underlying the disruption of Cu homeostasis in critical organs, such as the brain, remain unclear. In this study, we elucidated the molecular mechanisms of Cu imbalance in the brain of a valproic acid (VPA) mouse model along with the changes in specific metabolites. Significant alterations occurred in proteins associated with primary Cu-related metabolism in specific regions of the brain (prefrontal cortex, amygdala, cerebellum, and hippocampus), resulting in a direct elevation of Cu ions within the brain tissues (control: 5.05 ± 0.61 μg/g vs model: 6.28 ± 0.81 μg/g, p = 0.015). Furthermore, the brain metabolic profiles revealed significant upregulation of lipids, particularly phospholipid metabolites. Typical neurotransmitters, for example, dopamine (DA) (p < 0.0001) and serotonin (5-HT) (p = 0.02) were upregulated in amygdala. Other small metabolites like glutathione (GSH) (p = 0.0004) also exhibited notable variation in brain. The potential impact of Cu toxicity on the signaling pathways of key metabolites was then evaluated, providing new insights into the role of Cu in metabolism of neurotransmitters in the brain. Our finding sheds molecular aberrations associated with essential element metabolism in the brain, providing new elemental perspectives for understanding the pathogenic mechanisms underlying ASD.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845267","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}

引用次数: 0

Pilot Screening of TREM1 Inhibitors in Cell-Based Reporter Assays Reflecting TREM1/DAP12 Receptor Assembly and Functionality. 在反映 TREM1/DAP12 受体组装和功能的细胞报告实验中试行筛选 TREM1 抑制剂。

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-16 DOI: 10.1021/acschemneuro.4c00694

Natalia Filippova, Roman Hromov, James Shi, Peter H King, Louis B Nabors

{"title":"Pilot Screening of TREM1 Inhibitors in Cell-Based Reporter Assays Reflecting TREM1/DAP12 Receptor Assembly and Functionality.","authors":"Natalia Filippova, Roman Hromov, James Shi, Peter H King, Louis B Nabors","doi":"10.1021/acschemneuro.4c00694","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00694","url":null,"abstract":"Proinflammatory TREM1 receptors expressed on myeloid-derived cells have recently been recognized as a new oncogenic target in cancer, including gliomas. They are established chemotherapeutic targets in neurodegenerative Parkinson's and Alzheimer's diseases, and they also contribute to stroke and sepsis severities. TREM1 activation requires the TREM1/DAP12 interaction for receptor clustering and signal transduction coordinated by TREM1 ligands. Here, we established the quantitative cell-based high-throughput split luciferase assays of DAP12 dimerization, TREM1 dimerization, and TREM1/DAP12 interaction that allow screening of the inhibitory compounds with quantitative dose-responses, IC50 values, and specificity evaluation. The assays are based on the reconstitution of firefly luciferase activity during DAP12 dimerization, TREM1 dimerization, and TREM1/DAP12 interaction, leading to robust luminescence signals in the presence of luciferin. The ligand-dependent and -independent SCHOOL TREM1 inhibitory peptides were utilized for assay validation. Our pilot screen identified several compound scaffolds disrupting DAP12 dimerization, TREM1 dimerization, and the TREM1/DAP12 interaction. The compound potential mechanisms of action and binding sites in the TREM1 and DAP12 complexes were revealed using CB-Dock2 docking software. To our knowledge, this is the first report providing the first generation of pharmacological modulators for TREM1 receptors.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142826639","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}

引用次数: 0

S32, a Novel 3-Acetylaminocoumarin Compound, Exerts Neuroprotective Effects through the Inhibition of Neuroinflammation and Oxidative Stress In Vitro and In Vivo.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-12 DOI: 10.1021/acschemneuro.4c00742

Xiao Zhang, Jiaqi Li, Jie Zhao, Ruting Liu, Sa Wang, Zhuang Liu, Xuehua Sun, Minghui Li, Yan Ren, Mingna Sun, Zhipeng Li

{"title":"S32, a Novel 3-Acetylaminocoumarin Compound, Exerts Neuroprotective Effects through the Inhibition of Neuroinflammation and Oxidative Stress In Vitro and In Vivo.","authors":"Xiao Zhang, Jiaqi Li, Jie Zhao, Ruting Liu, Sa Wang, Zhuang Liu, Xuehua Sun, Minghui Li, Yan Ren, Mingna Sun, Zhipeng Li","doi":"10.1021/acschemneuro.4c00742","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00742","url":null,"abstract":"Neuroinflammation and oxidative stress are key factors leading to neuronal injury. In this study, we investigated the role of S32, a novel 3-acetylaminocoumarin compound, in ameliorating neuronal injury induced by neuroinflammation and oxidative stress in vitro and in vivo. First, we found that S32 reduced the expression levels of p-P65 and p-P38, inhibited the nuclear translocation of P65, and lowered the levels of pro-inflammatory factors in LPS-induced BV2 cells, which indicated that S32 had an antineuroinflammatory effect. Second, BV2 cell culture medium was used as the conditioned medium to establish a model of oxidative damage in PC12 cells. It was found that S32 reduced the level of ROS and increased mitochondrial membrane potential of PC12 cells, which indicated that S32 can protect PC12 cells against conditioned medium-induced injury. Next, we found that S32 inhibited the decrease of cell viability of PC12 cells caused by H2O2, inhibited nuclear damage, decreased the level of ROS, increased MMP, activated the AKT and ERK pathways, increased Bcl-2 levels, and decreased Bax and Cleaved-Caspase3 expression levels, indicating that S32 ameliorated the damaging effects of H2O2-induced PC12 cells. Finally, we found that S32 exerted the antineuroinflammatory and apoptosis-inhibiting effects in LPS-induced mice. In conclusion, this study first demonstrated that S32, a novel 3-acetylaminocoumarin compound, can reduce neuroinflammation and neuroinflammation-induced neuronal injury, exerting an indirect protective effect on neurons, and also exert a direct protective effect on neurons by reducing oxidative stress.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811407","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}

引用次数: 0

Discovery of Dual Targeting GSK-3β/HIV-1 Reverse Transcriptase Inhibitors as Neuroprotective Antiviral Agents.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-11 DOI: 10.1021/acschemneuro.4c00725

Thane Jones, Renuka Raman, Ana C Puhl, Thomas R Lane, Olga Riabova, Elena Kazakova, Vadim Makarov, Sean Ekins

{"title":"Discovery of Dual Targeting GSK-3β/HIV-1 Reverse Transcriptase Inhibitors as Neuroprotective Antiviral Agents.","authors":"Thane Jones, Renuka Raman, Ana C Puhl, Thomas R Lane, Olga Riabova, Elena Kazakova, Vadim Makarov, Sean Ekins","doi":"10.1021/acschemneuro.4c00725","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00725","url":null,"abstract":"Glycogen synthase kinase-3 beta (GSK-3β or GSK-3B) is a serine-threonine kinase involved in various pathways and cellular processes. Alteration in GSK-3β activity is associated with several neurological diseases including Alzheimer's disease (AD), bipolar disorder, and rare diseases like Rett syndrome. GSK-3β is also implicated in HIV-associated dementia (HAD), as it is upregulated in HIV-1-infected cells and plays a role in neuronal dysfunction. Therefore, a small molecule that can inhibit both GSK-3β and HIV-1 reverse transcriptase could offer neuroprotective therapy for patients suffering from HIV-1. Despite this, there are no known GSK-3β inhibitors currently approved, thus prompting us to screen our panel of various antiviral compounds against this kinase to better understand its structure-activity relationship. We show for the first time that the approved drugs, etravirine and rilpivirine, possess GSK-3β activity (IC50 619 nM and 502 nM, respectively). We have also identified 3 lead molecules exhibiting IC50 < 1 μM (11726169, 12326205, and 12326207), with compound 11726169 being the most potent in vitro GSK-3β inhibitor (IC50 = 12.1 nM). We also describe the generation of machine learning models for GSK-3β inhibition and their validation with our data as an external test set and propose their use for the future optimization of such inhibitors.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811406","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}

引用次数: 0

Structure-Activity Relationships and Molecular Pharmacology of Positive Allosteric Modulators of the Mu-Opioid Receptor.

IF 4.1 3区医学

ACS Chemical Neuroscience Pub Date : 2024-12-11 DOI: 10.1021/acschemneuro.4c00541

Mengchu Li, Xinmin Gan, Kun Liu, Rajeswaran Walajapet, M Alex Stanczyk, Hannah C Stewart, Jason C Rech, Andrew D White, John R Traynor

{"title":"Structure-Activity Relationships and Molecular Pharmacology of Positive Allosteric Modulators of the Mu-Opioid Receptor.","authors":"Mengchu Li, Xinmin Gan, Kun Liu, Rajeswaran Walajapet, M Alex Stanczyk, Hannah C Stewart, Jason C Rech, Andrew D White, John R Traynor","doi":"10.1021/acschemneuro.4c00541","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00541","url":null,"abstract":"Positive allosteric modulation of the mu-opioid receptor is a promising strategy to address the ever-growing problem of acute and chronic pain management. Positive allosteric modulators (PAMs) of the mu-opioid receptor could be employed to enhance the efficacy of endogenous opioid peptides to a degree that provides pain relief without the need for traditional opioid drugs. Alternatively, PAMs might be used to enhance the action of opioid drugs and so provide an opioid-sparing effect, allowing for the use of lower doses of opioid agonists and potentially decreasing associated side effects. BMS-986122 (2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl)-sulfonyl]-thiazolidine) has been previously identified as a PAM of the mu-opioid receptor. In the present work, we have designed and synthesized 33 analogs of BMS-986122 to explore the structure-activity relationships of this scaffold and confirm its allosteric mechanism of action. Among several newly identified modulators, the most promising compound (14b) had improved activity to increase the in vitro potency of the standard mu-opioid agonist DAMGO and showed in vivo activity in mice to enhance the antinociceptive action of morphine.","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811408","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}

引用次数: 0