ACS Chemical Neuroscience最新文献

{"title":"Classics in Chemical Neuroscience: Medetomidine","authors":"Pedro de Andrade Horn,&nbsp;Tomayo I. Berida,&nbsp;Lauren C. Parr,&nbsp;Jacob L. Bouchard,&nbsp;Navoda Jayakodiarachchi,&nbsp;Daniel C. Schultz,&nbsp;Craig W. Lindsley and Morgan L. Crowley*,&nbsp;","doi":"10.1021/acschemneuro.4c0058310.1021/acschemneuro.4c00583","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00583https://doi.org/10.1021/acschemneuro.4c00583","url":null,"abstract":"<p >Medetomidine is an FDA-approved α₂-adrenoreceptor (α₂-AR) agonist used as a veterinary sedative due to its analgesic, sedative, and anxiolytic properties. While it is marketed for veterinary use as a racemic mixture under the brand name Domitor, the pharmacologically active enantiomer, dexmedetomidine, is approved for sedation and analgesia in the hospital setting. Medetomidine has recently been detected in the illicit drug supply alongside fentanyl, xylazine, cocaine, and heroin, producing pronounced sedative effects that are not reversed by naloxone. The pharmacological effects along with the low cost of supply and lack of regulation for medetomidine has made it a target for misuse. Since 2022, medetomidine has been found as an adulterant in samples of seized drugs, as well as in toxicological analyses of patients admitted to the emergency department after suspected overdoses across several U.S. states and Canada. This Review will discuss the history, chemistry, structure–activity relationships, drug metabolism and pharmacokinetics (DMPK), pharmacology, and emergence of medetomidine as an adulterant in drug mixtures in the context of the current opioid drug crisis.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00583","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585854","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":"Unique Glycans in Synaptic Glycoproteins in Mouse Brain","authors":"Maxence Noel,&nbsp;Suttipong Suttapitugsakul,&nbsp;Mohui Wei,&nbsp;Catherine Tilton,&nbsp;Akul Y. Mehta,&nbsp;Yasuyuki Matsumoto,&nbsp;Jamie Heimburg-Molinaro,&nbsp;Robert G. Mealer and Richard D. Cummings*,&nbsp;","doi":"10.1021/acschemneuro.4c0039910.1021/acschemneuro.4c00399","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00399https://doi.org/10.1021/acschemneuro.4c00399","url":null,"abstract":"<p >The synapse is an essential connection between neuronal cells in which the membrane and secreted glycoproteins regulate neurotransmission. The post-translational modifications of glycoproteins with carbohydrates, although essential for their functions as well as their specific localization, are not well understood. Oddly, whereas galactose addition to glycoproteins is required for neuronal functions, galactosylation is severely restricted for Asn-linked on N-glycans in the brain, and genetic evidence highlights the important roles of galactose in brain functions and development. To explore this novel glycosylation, we exploited an orthogonal technology in which a biotinylated sialic acid derivative (CMP-biotin-Sia) is transferred to terminally galactosylated proteins by a recombinant sialyltransferase (rST6Gal1). This approach allowed us to identify the carrier proteins as well as their localization on brain sections. Immunohistochemical analysis of the biotinylated glycoproteins in brain sections demonstrates that they are largely positioned in the pre- and postsynaptic membranes. Consistent with this positioning, glycoproteomic analyses of the labeled glycoproteins identified a number of them that are involved in synaptic function, cell adhesion, and extracellular matrix interactions. The discovery of these galactosylated N-glycoproteins and their relative confinement to synapses provide novel insights into the unusual and specific nature of protein glycosylation in the brain.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585849","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":"Proteome Aggregation in Cells Derived from Amyotrophic Lateral Sclerosis Patients for Personalized Drug Evaluation","authors":"Carmen Pérez de la Lastra Aranda,&nbsp;Carlota Tosat-Bitrián,&nbsp;Gracia Porras,&nbsp;Ruxandra Dafinca,&nbsp;Diego Muñoz-Torrero,&nbsp;Kevin Talbot,&nbsp;Ángeles Martín-Requero,&nbsp;Ana Martínez and Valle Palomo*,&nbsp;","doi":"10.1021/acschemneuro.4c0032810.1021/acschemneuro.4c00328","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00328https://doi.org/10.1021/acschemneuro.4c00328","url":null,"abstract":"<p >Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that currently lacks effective therapy. Given the heterogeneity of clinical and molecular profiles of ALS patients, personalized diagnostics and pathological characterization represent a powerful strategy to optimize patient stratification, thereby enabling personalized treatment. Immortalized lymphocytes from sporadic and genetic ALS patients recapitulate some pathological hallmarks of the disease, facilitating the fundamental task of drug screening. However, the molecular aggregation of ALS has not been characterized in this patient-derived cellular model. Indeed, protein aggregation is one of the most prominent features of neurodegenerative diseases, and therefore, models to test drugs against personalized pathological aggregation could help discover improved therapies. With this work, we aimed to characterize the aggregation profile of ALS immortalized lymphocytes and test several drug candidates with different mechanisms of action. In addition, we have evaluated the molecular aggregation in motor neurons derived from two hiPSC cell lines corresponding to ALS patients with different mutations in <i>TARDBP</i>. The results provide valuable insight into the different characterization of sporadic and genetic ALS patients’ immortalized lymphocytes, their differential response to drug treatment, and the usefulness of proteome homeostasis characterization in patients’ cells.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585848","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":"Propionate Decreases Microglial Activation but Impairs Phagocytic Capacity in Response to Aggregated Fibrillar Amyloid Beta Protein","authors":"Andrew Gold,&nbsp;Sarah Kaye,&nbsp;Jie Gao and Jiangjiang Zhu*,&nbsp;","doi":"10.1021/acschemneuro.4c0037010.1021/acschemneuro.4c00370","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00370https://doi.org/10.1021/acschemneuro.4c00370","url":null,"abstract":"<p >Microglia, the innate immune cell of the brain, are a principal player in Alzheimer’s disease (AD) pathogenesis. Their surveillance of the brain leads to interaction with the protein aggregates that drive AD pathogenesis, most notably Amyloid Beta (Aβ). Microglia attempt to clear and degrade Aβ using phagocytic machinery, spurring damaging neuroinflammation in the process. Thus, modulation of the microglial response to Aβ is crucial in mitigating AD pathophysiology. SCFAs, microbial byproducts of dietary fiber fermentation, are blood–brain barrier permeable molecules that have recently been shown to modulate microglial function. It is unclear whether propionate, one representative SCFA, has beneficial or detrimental effects on microglia in AD. Thus, we investigated its impact on microglial Aβ response in vitro. Using a multiomics approach, we characterized the transcriptomic, metabolomic, and lipidomic responses of immortalized murine microglia following 1 h of Aβ stimulation, as well as characterizing Aβ phagocytosis and secretion of reactive nitrogen species. Propionate blunted the early inflammatory response driven by Aβ, downregulating the expression of many Aβ-stimulated immune genes, including those regulating inflammation, the immune complement system, and chemotaxis. Further, it reduced the expression of <i>Apoe</i> and inflammation-promoting Aβ-binding scavenger receptors such as <i>Cd36</i> and <i>Msr1</i> in favor of inflammation-dampening <i>Lpl</i>, although this led to impaired phagocytosis. Finally, propionate shifted microglial metabolism, altering phospholipid composition and diverting arginine metabolism, resulting in decreased nitric oxide production. Altogether, our data demonstrate a modulatory role of propionate on microglia that may dampen immune activation in response to Aβ, although at the expense of phagocytic capacity.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585691","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":"Alzheimer’s Disease: Exploring the Landscape of Cognitive Decline","authors":"Rumiana Tenchov,&nbsp;Janet M. Sasso and Qiongqiong Angela Zhou*,&nbsp;","doi":"10.1021/acschemneuro.4c0033910.1021/acschemneuro.4c00339","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00339https://doi.org/10.1021/acschemneuro.4c00339","url":null,"abstract":"<p >Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and impaired daily functioning. The pathology of AD is marked by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction. Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD. Currently available treatments provide symptomatic relief but do not halt disease progression. Research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD. Advances in identification and validation of reliable biomarkers for AD hold great promise for enhancing early diagnosis, monitoring disease progression, and assessing treatment response in clinical practice in effort to alleviate the burden of this devastating disease. In this paper, we analyze data from the CAS Content Collection to summarize the research progress in Alzheimer’s disease. We examine the publication landscape in effort to provide insights into current knowledge advances and developments. We also review the most discussed and emerging concepts and assess the strategies to combat the disease. We explore the genetic risk factors, pharmacological targets, and comorbid diseases. Finally, we inspect clinical applications of products against AD with their development pipelines and efforts for drug repurposing. The objective of this review is to provide a broad overview of the evolving landscape of current knowledge regarding AD, to outline challenges, and to evaluate growth opportunities to further efforts in combating the disease.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00339","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585845","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":"Interactions of Polychlorinated Biphenyls and Their Metabolites with the Brain and Liver Transcriptome of Female Mice","authors":"Amanda J. Bullert,&nbsp;Hui Wang,&nbsp;Anthony E. Valenzuela,&nbsp;Kari Neier,&nbsp;Rebecca J. Wilson,&nbsp;Jessie R. Badley,&nbsp;Janine M. LaSalle,&nbsp;Xin Hu,&nbsp;Pamela J. Lein and Hans-Joachim Lehmler*,&nbsp;","doi":"10.1021/acschemneuro.4c0036710.1021/acschemneuro.4c00367","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00367https://doi.org/10.1021/acschemneuro.4c00367","url":null,"abstract":"<p >Exposure to polychlorinated biphenyls (PCBs) is linked to neurotoxic effects. This study aims to close knowledge gaps regarding the specific modes of action of PCBs in female C57BL/6J mice (&gt;6 weeks) orally exposed for 7 weeks to a human-relevant PCB mixture (MARBLES mix) at 0, 0.1, 1, and 6 mg/kg body weight/day. PCB and hydroxylated PCB (OH-PCBs) levels were quantified in the brain, liver, and serum; RNA sequencing was performed in the striatum, prefrontal cortex, and liver, and metabolomic analyses were performed in the striatum. Profiles of PCBs but not their hydroxylated metabolites were similar in all tissues. In the prefrontal cortex, PCB exposure activated the oxidative phosphorylation respiration pathways, while suppressing the axon guidance pathway. PCB exposure significantly changed the expression of genes associated with neurodevelopmental and neurodegenerative diseases in the striatum, impacting pathways like growth hormone synthesis and dendrite development. PCBs did not affect the striatal metabolome. In contrast to the liver, which showed activation of metabolic processes following PCB exposure and the induction of cytochrome P450 enzymes, the expression of xenobiotic processing genes was not altered by PCB exposure in either brain region. Network analysis revealed complex interactions between individual PCBs (e.g., PCB28 [2,4,4′-trichlorobiphenyl]) and their hydroxylated metabolites and specific differentially expressed genes (DEGs), underscoring the need to characterize the association between specific PCBs and DEGs. These findings enhance the understanding of PCB neurotoxic mechanisms and their potential implications for human health.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00367","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585846","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":"Novel Piperazine Based Compounds Target Alzheimer’s Disease Relevant Amyloid β42 and Tau Derived Peptide AcPHF6, and the Lead Molecule Increases Viability in the Flies Expressing Human Tau Protein","authors":"Christopher Armstrong,&nbsp;Dan Luo,&nbsp;Anna Gretzinger,&nbsp;Deepti Pandey,&nbsp;Andrew Lipchik,&nbsp;Sokol V. Todi and Aloke K. Dutta*,&nbsp;","doi":"10.1021/acschemneuro.4c0022010.1021/acschemneuro.4c00220","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00220https://doi.org/10.1021/acschemneuro.4c00220","url":null,"abstract":"<p >Alzheimer’s disease (AD) is the leading form of dementia in the United States and the world. The pathophysiology of AD is complex and multifaceted. Accumulation of senile plaques and neurofibrillary tangles (NFTs) are hallmarks of AD. The aggregation of amyloid β (senile plaques) and tau tangles (NFTs) results in the death of neurons in the cortex and hippocampus, which manifests itself in cognitive decline and memory loss. Current therapies rely on conventional approaches that have only treated the underlying symptoms without disease modification. Data from clinical studies point to a complex role of amyloid β (Aβ) in a way that enhances the tau phenotype throughout the disease process. To address the co-pathogenic role of Aβ and tau, we undertook development of multitarget compounds aiming at both tau and Aβ to slow or stop disease progression and provide neuroprotection. Here, we demonstrate a dose-dependent effect of the novel test compounds that inhibit aggregation of AcPHF6 (a shorter version of tau protein) and Aβ_1–42 peptides in thioflavin T fluorescent assays. The compounds were also shown to disaggregate preformed aggregates dose dependently. To further validate these findings, circular dichroism experiments were carried out to examine the nature of inhibition. Additionally, transmission electron microscopy experiments were carried out to gain insights into the morphologies of aggregates obtained from dose-dependent inhibition of AcPHF6 and Aβ_1–42 as well as dissociation of preformed aggregates from these peptides. Compounds <b>D-687</b> and <b>D-688</b> reversed Aβ_1–42 induced toxicity in SH-SH5Y cells, significantly demonstrating neuroprotective properties. Finally, in a study with <i>Drosophila melanogaster</i> expressing human tau protein isoform (2N4R) in all the neurons, compound <b>D-688</b> significantly increased the survival of flies compared to vehicle treated controls. Future studies will further examine the neuroprotective properties of these lead compounds in various animal models.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585710","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":"Classics in Chemical Neuroscience: Tianeptine","authors":"Yu Nishio,&nbsp;Craig W. Lindsley and Aaron M. Bender*,&nbsp;","doi":"10.1021/acschemneuro.4c0051910.1021/acschemneuro.4c00519","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00519https://doi.org/10.1021/acschemneuro.4c00519","url":null,"abstract":"<p >Tianeptine (<b>1</b>) is an unusual antidepressant in that its mechanism of action appears to be independent from any activity at serotonin receptors or monoamine transporters. In fact, tianeptine has been shown to be a moderately potent agonist for the mu opioid receptor (MOR) and to a lesser extent the delta opioid receptor (DOR). Additionally, tianeptine’s efficacy may be related to its action on glutamate-mediated pathways of neuroplasticity. Regardless of which neurotransmitter system is primarily responsible for the observed efficacy, the MOR agonist activity is problematic with respect to abuse liability. Increasing numbers of case reports have demonstrated that tianeptine is indeed being used recreationally at doses far beyond what are considered therapeutically relevant or safe, and scheduling reclassifications or outright bans on tianeptine products are ongoing around the world. It is the aim of this review to discuss the medicinal chemistry and pharmacology of tianeptine and to summarize this intriguing discrepancy between tianeptine’s historical use as a safe and effective antidepressant and its emerging potential for abuse.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00519","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585676","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":"Comment on “Extracellular Vesicles Slow Down Aβ(1–42) Aggregation by Interfering with the Amyloid Fibril Elongation Step”","authors":"Mohsin Shafiq,&nbsp;Andreu Matamoros-Angles,&nbsp;Sussane Caroline Meister and Markus Glatzel*,&nbsp;","doi":"10.1021/acschemneuro.4c0060110.1021/acschemneuro.4c00601","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00601https://doi.org/10.1021/acschemneuro.4c00601","url":null,"abstract":"<p >Halipi et al. explored the impact of extracellular vesicles (EVs) on amyloid-β (Aβ) aggregation. They concluded that EVs reduce Aβ aggregation, as seen by shorter and thicker fibrils. While we agree with the complex role of EVs in Alzheimer’s disease, we are sceptical of the claim that EVs slow down Aβ aggregation, noting missing key references. Previous literature rather suggests that EVs (derived from neuronal cell lines) accelerate the process of Aβ fibrillation and plaque formation. Halipi et al.’s findings may be skewed due to the lack of essential neuronally expressed Aβ-binding partners, like the prion protein (PrP^C) in their EV samples. The commentary, in the light of included original experiments and cited literature, suggests that membrane proteins like PrP^C are crucial to fully understand the role of EVs in Aβ aggregation, and Halipi et al.’s conclusions should be reexamined in light of these factors.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585764","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":"Development of Tetrahydroquinoline-Based Inhibitors for Chronic Pain","authors":"Ketul V. Patel,&nbsp;Vinicius M. Gadotti,&nbsp;Agustin Garcia-Caballero,&nbsp;Flavia T. T. Antunes,&nbsp;Md Yousof Ali,&nbsp;Gerald W. Zamponi* and Darren J. Derksen*,&nbsp;","doi":"10.1021/acschemneuro.4c0031610.1021/acschemneuro.4c00316","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00316https://doi.org/10.1021/acschemneuro.4c00316","url":null,"abstract":"<p >Chronic pain affects a substantial portion of the population, posing a significant health challenge. Current treatments often come with limitations and side effects, necessitating novel therapeutic approaches. Our study focuses on disrupting the Cav3.2-USP5 interaction as a strategy for chronic pain management. Through structure–activity relationship studies of a tetrahydroquinoline (THQ) scaffold, we identified a family of lead molecules that demonstrated potent inhibition of the Cav3.2-USP5 interaction. In vitro pharmacokinetic assessments and in vivo studies support the efficacy and drug-like properties of the lead compounds in mouse models of acute and chronic pain. Dependence on the Cav3.2 channels was validated in Cav3.2 null mice, consistent with the proposed mode of action of these small molecules. These findings provide a novel chronic pain treatment strategy, highlighting the potential of these small molecules for further development.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142437115","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}