ACS Chemical Neuroscience最新文献

{"title":"Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Restricts Inflammatory Progression through Limiting Macrophage Infiltration in DRG and Sciatic Nerve during Diabetic Peripheral Neuropathy.","authors":"Peng Dai, Peng Wang, Xin Chen, Shuyun Feng, Fancan Wu, Xueqin Zheng, Zaisheng Qin","doi":"10.1021/acschemneuro.5c00021","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00021","url":null,"abstract":"<p><p>Diabetic peripheral neuropathy (DPN) is a prevalent complication affecting over half of individuals with diabetes. This study investigates the role of mesencephalic Astrocyte-derived neurotrophic factor (MANF) in DPN progression and its potential as a therapeutic target. Using a streptozotocin (STZ)-induced diabetic mouse model, we analyzed MANF expression in the dorsal root ganglia (DRG) and sciatic nerve and assessed the effects of recombinant human MANF (rhMANF) administration on DPN symptoms. Our findings show significant upregulation of MANF protein levels in the DRG of diabetic mice, along with an increased presence of MANF-expressing macrophages in both the DRG and sciatic nerve. Intravenous administration of rhMANF from Day 7 to Day 21 post-STZ injection yielded multiple beneficial outcomes. Notably, rhMANF treatment alleviated mechanical hypoalgesia, as measured by the paw mechanical withdrawal threshold (PMWT), and enhanced sciatic nerve conduction, improving motor nerve conduction velocity (MNCV). Additionally, it increased intradermal nerve density, indicated by more PGP9.5-positive nerve fibers in the plantar skin of treated diabetic mice. These improvements were associated with reduced macrophage infiltration in the DRG and sciatic nerve, marked by fewer CD68 and Iba-1 positive cells, and inhibition of inflammatory signaling pathways. Specifically, rhMANF treatment decreased NF-κB p65 phosphorylation and suppressed p38 MAPK phosphorylation, indicating reduced inflammation. In summary, our research underscores MANF's potential as a novel therapeutic target for DPN, particularly due to its anti-inflammatory properties. Further exploration of MANF could lead to the development of more effective treatments for this debilitating aspect of diabetes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456260","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":"Blocking the p38 MAPK Signaling Pathway in the Rat Hippocampus Alleviates the Depressive-like Behavior Induced by Spinal Cord Injury.","authors":"Zhiping Xie, Tianqi Xu, Jiwu Chen, Yongping Gui, Dengfeng Wan, Meihua Li","doi":"10.1021/acschemneuro.4c00413","DOIUrl":"10.1021/acschemneuro.4c00413","url":null,"abstract":"<p><p>Patients with spinal cord injury (SCI) may develop depression, which can affect their rehabilitation. However, the underlying mechanism of depression in SCI patients remains unclear. Previous studies have revealed increased p38 MAPK phosphorylation in the rat hippocampus after SCI, accompanied by depression-like behaviors. However, the role of the p38 MAPK signaling pathway in SCI-induced depression remains unclear. In this study, we used an aneurysm clip-induced rat SCI model to investigate whether p38 MAPK phosphorylation in the hippocampus is associated with depression-like behaviors in rats after SCI. Behavioral testing revealed that SB203580, a p38 MAPK signaling inhibitor, reduced depression-like behaviors. Western blotting and morphological analyses showed that SB203580 inhibited the activation of microglia and astrocytes in the hippocampus after SCI. Additionally, SB203580 reduced the expression of tumor necrosis factor α and increased p38 MAPK phosphorylation and the number of bromodeoxyuridine-positive cells in the hippocampus. These findings suggest that SB203580 can inhibit hippocampal remodeling and the neuroimmune response in the rat hippocampus after SCI. Therefore, the phosphorylation of p38 MAPK in the hippocampus plays a key role in the depression-like behaviors induced by SCI. The inhibition of p38 MAPK phosphorylation may represent a mechanism to protect against hippocampal injury induced by SCI.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"595-603"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051037","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":"Chemoproteomics Sheds Light on Epigenetic Targets of [¹¹C]Martinostat in the Human Brain.","authors":"Mary C Catanese, Yvonne E Klingl, Tonya M Gilbert, Martin G Strebl-Bantillo, Christina R Hartigan, Monica Schenone, Jacob M Hooker","doi":"10.1021/acschemneuro.4c00781","DOIUrl":"10.1021/acschemneuro.4c00781","url":null,"abstract":"<p><p>Initiation of research programs to investigate binding specificity based on in vivo positron emission tomography (PET) imaging results can provide rich opportunities to improve data interpretation, gain biological insight, and inform hypothesis development. Here, we profile the binding specificity of the neuroepigenetic imaging probe, [¹¹C]Martinostat. In vivo neuroimaging studies using [¹¹C]Martinostat have uncovered differential regional uptake in relation to age and biological sex and in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and low-back pain compared to healthy controls. Previous studies using recombinant proteins and thermal shift assays in postmortem tissue indicate that [¹¹C]Martinostat engages class I and putatively class IIb histone deacetylases (HDACs). While HDACs serve multiple functions, including regulation of chromatin remodeling and gene transcription, it is not known how differences in HDAC expression may arise across brain regions. HDACs functionally interact with a diverse array of multisubunit complexes, and engagement with associated binding partners may contribute to these differences. To further assess target engagement of [¹¹C]Martinostat, we designed a synthetic probe based on the inhibitor structural scaffold for use in competition experiments followed by proteomic analysis in postmortem tissue. The synthetic probe, called Compound 4, appears to interact with the class I HDAC paralog HDAC2 and the class IIb paralog HDAC6 in a robust manner. We also uncovered unique interacting partners, including synaptic proteins from the synaptotagmin (SYT) family of proteins and neuronal pentraxin 2 (NPTX2). Further work to investigate HDAC associations with interacting proteins across regions of the human brain is needed to better understand neuroepigenetic dysregulation in psychiatric and neurological conditions.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"723-731"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254074","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":"Molecular Insights into α-Synuclein Fibrillation: A Raman Spectroscopy and Machine Learning Approach.","authors":"Nathan P Coles, Suzan Elsheikh, Agathe Quesnel, Lucy Butler, Claire Jennings, Chaimaa Tarzi, Ojodomo J Achadu, Meez Islam, Karunakaran Kalesh, Annalisa Occhipinti, Claudio Angione, Jon Marles-Wright, David J Koss, Alan J Thomas, Tiago F Outeiro, Panagiota S Filippou, Ahmad A Khundakar","doi":"10.1021/acschemneuro.4c00726","DOIUrl":"10.1021/acschemneuro.4c00726","url":null,"abstract":"<p><p>The aggregation of α-synuclein is crucial to the development of Lewy body diseases, including Parkinson's disease and dementia with Lewy bodies. The aggregation pathway of α-synuclein typically involves a defined sequence of nucleation, elongation, and secondary nucleation, exhibiting prion-like spreading. This study employed Raman spectroscopy and machine learning analysis, alongside complementary techniques, to characterize the biomolecular changes during the fibrillation of purified recombinant wild-type α-synuclein protein. Monomeric α-synuclein was produced, purified, and subjected to a 7-day fibrillation assay to generate preformed fibrils. Stages of α-synuclein fibrillation were analyzed using Raman spectroscopy, with aggregation confirmed through negative staining transmission electron microscopy, mass spectrometry, and light scattering analyses. A machine learning pipeline incorporating principal component analysis and uniform manifold approximation and projection was used to analyze the Raman spectral data and identify significant peaks, resulting in differentiation between sample groups. Notable spectral shifts in α-synuclein were found in various stages of aggregation. Early changes (D1) included increases in α-helical structures (1303, 1330 cm^-1) and β-sheet formation (1045 cm^-1), with reductions in COO^- and CH₂ bond regions (1406, 1445 cm^-1). By D4, these structural shifts persist with additional β-sheet features. At D7, a decrease in β-sheet H-bonding (1625 cm^-1) and tyrosine ring breathing (830 cm^-1) indicates further structural stabilization, suggesting a shift from initial helical structures to stabilized β-sheets and aggregated fibrils. Additionally, alterations in peaks related to tyrosine, alanine, proline, and glutamic acid were identified, emphasizing the role of these amino acids in intramolecular interactions during the transition from α-helical to β-sheet conformational states in α-synuclein fibrillation. This approach offers insight into α-synuclein aggregation, enhancing the understanding of its role in Lewy body disease pathophysiology and potential diagnostic relevance.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"687-698"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Muscle Matters: Transforming Amyotrophic Lateral Sclerosis Diagnostics with Next-Gen Biosensors and Smart Detection.","authors":"Saumitra Singh, Sameer Khan, Shina Khan, Osheen Ansari, Nitesh Malhotra, Sudheesh K Shukla, Jagriti Narang","doi":"10.1021/acschemneuro.4c00664","DOIUrl":"10.1021/acschemneuro.4c00664","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that primarily targets the motor system, causing patients' speech and swallowing ability to rapidly deteriorate. Although ALS is usually classified into familial and sporadic forms, diagnosing it can be extremely difficult due to the absence of definitive biomarkers, often resulting in delays in diagnosis. Current diagnostic practices rely heavily on clinical assessments that indicate damage to both upper motor neurons (UMNs) and lower motor neurons (LMNs). This includes comprehensive physical examinations, electromyography (EMG) to assess neuromuscular function, and the exclusion of other similar conditions such as cervical spondylotic myelopathy, multifocal motor neuropathy, and Kennedy's disease through appropriate diagnostic procedures. The urgent need for specific biomarkers is critical for timely diagnosis and therapeutic advancements in ALS management. While many recent developments in research have not yet translated into direct patient benefits, the recognition of ALS as a complex disease is beginning to influence clinical practice significantly. Optimal management strategies emphasize on symptom control and improving the quality of life for patients within a holistic healthcare framework. This review provides a comprehensive overview of ALS, delving into its pathophysiology, clinical symptoms, and the latest advancements in detection methods that utilize traditional approaches, innovative biosensors, and smart diagnostic technologies. It discusses various treatment options available for ALS while exploring future developments that may enhance patient screening and improve clinical outcomes. By integrating assessments into the underlying mechanisms of the disease with cutting-edge diagnostic approaches, this review aims to contribute meaningfully to ongoing efforts to optimize ALS management and therapeutic strategies, ultimately improving patient care and outcomes.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"563-587"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254077","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":"Exosomal PINK1 from Human Umbilical Cord Mesenchymal Stem Cells Attenuates Neurological Deficits and Inflammatory Responses after Intracerebral Hemorrhage in Mice.","authors":"Jianliang Li, Liang Yang, Lin Zhao, Jingchen Li","doi":"10.1021/acschemneuro.4c00575","DOIUrl":"10.1021/acschemneuro.4c00575","url":null,"abstract":"<p><p>This study investigated the therapeutic potential of exosomes from human umbilical cord mesenchymal stem cells (huMSCs), focusing on PTEN-induced kinase 1 (PINK1) and its impact on exosome efficacy. Postmodification, exosomes were administered to a murine model of intracranial hemorrhage (ICH). Assessments included brain edema, neurological function, anxiety-like behaviors, inflammatory responses, and microglial polarization. We observed that administration of exosomes from control huMSCs significantly reduced brain water content, indicating a reduction in brain edema, as quantitatively assessed through water content analysis. Neurological function, evaluated using a standard scoring system, showed marked improvement in animals treated with control exosomes compared with those receiving PINK1-deficient exosomes, highlighting the importance of PINK1 in mediating neurological recovery. Additionally, control exosomes substantially decreased anxiety-like behaviors in the Open Field Test, demonstrated by reduced immobility times and increased exploratory behavior. Inflammatory response assessments showed a favorable shift with decreased levels of pro-inflammatory cytokines (MCP-1, IL-1β, TNF-α) and increased levels of the anti-inflammatory cytokine IL-10 in the exosome-treated groups. Furthermore, analysis of microglial polarization revealed a shift toward the anti-inflammatory M2 phenotype, evidenced by decreased M1 markers (Cd86, Iba1) and increased M2 markers (Arg1, Cd206) in the control exosome-treated group. Taken together, we found that PINK1-deficient exosomes showed reduced therapeutic efficacy in ICH treatment compared with the exosomes with normal PINK1 expression. Our findings underscore the critical role of PINK1 in enhancing the therapeutic potential of huMSC-derived exosomes in ICH treatment.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"619-627"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187531","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":"Ratiometric Imaging for Quantification of Elevated Ca²⁺ in Neurons Using Synthetic Low-Affinity Fluorescent Probe.","authors":"Yuzuka Kuronuma, Yutaka Shindo, Rei Kumada, Akihiro Sakama, Daniel Citterio, Kotaro Oka, Yuki Hiruta","doi":"10.1021/acschemneuro.4c00668","DOIUrl":"10.1021/acschemneuro.4c00668","url":null,"abstract":"<p><p>The availability of various calcium ion (Ca²⁺) fluorescent probes has contributed to revealing physiological events related to intracellular Ca²⁺. However, conventional probes face challenges for quantitatively and selectively visualizing high Ca²⁺ concentrations in cells induced by any stimuli, including biomolecules or electrical signal that disrupt Ca²⁺ homeostasis. In this report, we designed and synthesized a low-affinity ratiometric Ca²⁺ probe, <b>KLCA-Fura</b>, utilizing <i>o</i>-aminophenol-<i>N,N</i>-diacetate-<i>O</i>-methylene-methylphosphinate (APDAP) as a ligand, for which we recently demonstrated the suitability as a new low-affinity ligand for Ca²⁺. <b>KLCA-Fura</b> showed a blue shift in excitation wavelength with increasing Ca²⁺ concentration based on the intramolecular charge transfer (ICT). Its affinity for Ca²⁺ is lower than commercially available conventional Ca²⁺ probes. Furthermore, the selectivity for Ca²⁺ and the fluorescence intensity were considered sufficient to accurately detect Ca²⁺. The corresponding acetoxymethyl ester, <b>KLCA-FuraAM</b>, was synthesized for intracellular imaging and applied to Ca²⁺ quantification in neurons. <b>KLCA-FuraAM</b> enabled quantitative ratiometric monitoring of the two-step Ca²⁺ concentration increase induced by glutamate stimulation. While this two-step response was not clearly observed with a commercially available low-affinity ratiometric Ca²⁺ probe, Fura-FF, <b>KLCA-FuraAM</b> has demonstrated the potential to quantitatively visualize the behavior of high Ca²⁺ concentrations. The ratiometric low-affinity Ca²⁺ probe, <b>KLCA-Fura</b>, is expected to be a powerful tool for discovering new functions of Ca²⁺ in neurons.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"649-658"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct Aggregation Behavior of <i>N</i>-Terminally Truncated Aβ_4-42 Over Aβ_1-42 in the Presence of Zn(II).","authors":"Chanju Na, Mingeun Kim, Gunhee Kim, Yuxi Lin, Young-Ho Lee, Wojciech Bal, Eunju Nam, Mi Hee Lim","doi":"10.1021/acschemneuro.4c00831","DOIUrl":"10.1021/acschemneuro.4c00831","url":null,"abstract":"<p><p>The deposition of amyloid-β (Aβ) aggregates and metal ions within senile plaques is a hallmark of Alzheimer's disease (AD). Among the modifications observed in Aβ peptides, <i>N</i>-terminal truncation at Phe4, yielding Aβ_4-x, is highly prevalent in AD-affected brains and significantly alters Aβ's metal-binding and aggregation profiles. Despite the abundance of Zn(II) in senile plaques, its impact on the aggregation and toxicity of Aβ_4-x remains unexplored. Here, we report the distinct aggregation behavior of <i>N</i>-terminally truncated Aβ, specifically Aβ_4-42, in the absence and presence of either Zn(II), Aβ seeds, or both, and compare it to that of full-length Aβ_1-42. Our findings reveal notable differences in the aggregation profiles of Aβ_4-42 and Aβ_1-42, largely influenced by their different Zn(II)-binding properties. These results provide insights into the mechanisms underlying the distinct aggregation behavior of truncated and full-length Aβ in the presence of Zn(II), contributing to a deeper understanding of AD pathology.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"732-744"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062120","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":"Synthesis and Evaluation of Benzylic ¹⁸F-Labeled <i>N</i>-Biphenylalkynyl Nipecotic Acid Derivatives for PET Imaging of GABA Transporter 1.","authors":"Niels Knippenberg, Matthias Bauwens, Alexandru Florea, Soma Rudi, Olaf Schijns, Govert Hoogland, Vincent Ornelis, Ronny Mohren, Michiel Vandenbosch, Felix M Mottaghy, Thomas J Cleij, Kasper Eersels, Bart van Grinsven, Hanne Diliën","doi":"10.1021/acschemneuro.4c00782","DOIUrl":"10.1021/acschemneuro.4c00782","url":null,"abstract":"<p><p>As the main inhibitory neurotransmission system, the GABAergic system poses an interesting yet underutilized target for molecular brain imaging. While PET imaging of postsynaptic GABAergic neurons has been accomplished using radiolabeled benzodiazepines targeting the GABA_A receptor, the development of presynaptic radioligands targeting GABA transporter 1 (GAT1) has been unsuccessful thus far. Therefore, we developed a novel GAT1-addressing radioligand and investigated its applicability as a PET tracer in rodents. We selected a lipophilic nipecotic acid scaffold that is known to bind selectively to GAT1 as the basis for our radioligand. To obtain the desired candidate radiotracer <b>[</b>^<b>18</b><b>F]4</b>, ester-protected radioligands <b>[</b>^<b>18</b><b>F]11a-b</b> were synthesized through aliphatic nucleophilic radiofluorination of the respective bromo-precursors, after which chemical deprotection was attempted using various conditions. Because these deprotections were unsuccessful, it was evaluated whether the ethyl ester <b>[</b>^<b>18</b><b>F]11a</b> could function as a prodrug and afford the active radioligand <b>[</b>^<b>18</b><b>F]4</b> after <i>in vivo</i> ester hydrolysis by esterases. Unfortunately, PET imaging studies in a rat model using <b>[</b>^<b>18</b><b>F]11a</b> showed no brain uptake of the radiotracer. Instead, significant uptake of radioactivity was observed in the liver and bones, the latter being caused by radiodefluorination of the PET tracer. Since the PET tracer developed in this study was found to be unstable, further efforts should investigate the development of a more stable GAT1-addressing PET tracer without the potential labile benzyl fluoride moiety. Moreover, as the still intact fraction of the radiotracer did not cross the BBB, options other than the prodrug approach should be considered to increase the BBB permeability of future GAT1 radioligands.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"711-722"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143057505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Further Optimization of the mGlu₁ PAM VU6024578/BI02982816: Discovery and Characterization of VU6033685.","authors":"Carson W Reed, Jacob F Kalbfleisch, Jeremy A Turkett, Trevor A Trombley, Paul K Spearing, Daniel H Haymer, Marc Quitalig, Jonathan W Dickerson, Daniel J Foster, Annie L Blobaum, Olivier Boutaud, Hyekyung P Cho, Colleen M Niswender, Jerri M Rook, Henning Priepke, Heiko Sommer, Stefan Scheuerer, Daniel Ursu, P Jeffrey Conn, Bruce J Melancon, Craig W Lindsley","doi":"10.1021/acschemneuro.5c00014","DOIUrl":"10.1021/acschemneuro.5c00014","url":null,"abstract":"<p><p>Herein, we report the further chemical optimization of the metabotropic glutamate receptor subtype 1 (mGlu₁) positive allosteric modulator (PAM) VU6024578/BI02982816 and the discovery of VU6033685/BI1752. PAM VU6033685/BI1752 was developed through an iterative process wherein, after the furanyl moiety (a potential toxicophore) was replaced by an <i>N</i>-linked pyrazole, a diversity screen identified a quinoline core, which was further truncated to a pyridine scaffold. PAM VU6033685/BI1752 proved to be a potent and selective mGlu₁ PAM with efficacy in both amphetamine-induced hyperlocomotion (AHL) and novel object recognition (NOR) with a clear pharmacokinetic-pharmacodynamic (PK/PD) relationship. VU6024578/BI02982816 was efficacious and well tolerated in rats but not dogs, whereas VU6033685/BI1752 elicited adverse events (AEs) in both rats and dogs. These AEs, noted in two distinct mGlu₁ PAM chemotypes, cast a shadow on an otherwise promising molecular target to address multiple symptom clusters in schizophrenic patients.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":" ","pages":"745-752"},"PeriodicalIF":4.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}