Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Preliminary pharmacokinetics and in vivo studies indicate analgesic and stress mitigation effects of a novel NMDA receptor modulator.","authors":"Blaise M Costa, De'Yana Hines, Nakia Phillip, Seth C Boehringer, Ramu Anandakrishnan, McAlister Council-Troche, Jennifer L Davis","doi":"10.1016/j.jpet.2025.103401","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103401","url":null,"abstract":"<p><p>N-methyl D-aspartate receptor (NMDAR) channel blockers produce analgesic and antidepressant effects by preferentially inhibiting the GluN2D subtype at lower doses. Given the distinct physiological role of GluN2 subunits, we hypothesized that compounds capable of simultaneously modulating GluN2A and GluN2D subtypes in opposite directions could serve as effective analgesics with minimal cognitive adverse effects. In this translational study, we investigated the in vivo effects of costa NMDAR stimulator 4 (CNS4), a recently discovered glutamate concentration-dependent NMDAR modulator. Pharmacokinetic data revealed that CNS4 reaches peak plasma and brain concentrations within 0.25 hours after intraperitoneal injection, with brain concentrations reaching values up to 8.4% of those in plasma (64.9 vs 5.47 μg/mL). Preliminary results showed that CNS4, a nonopioid compound, increased escape latency in mice during a hotplate assay by 1.74-fold compared with saline. In a fear conditioning experiment, CNS4 anecdotally reduced the electric shock sensation and significantly decreased stress-related defecation (fecal pellets: males, 21 vs 1; females, 19 vs 3). CNS4 also improved hyperarousal behavior (25 vs 4 jumps), without affecting fear memory parameters such as freezing episodes, duration, or latency. CNS4 caused no changes in locomotion across 8 of 9 parameters studied. Remarkably, approximately 50 hours after fear conditioning training, CNS4 prevented stress-induced excessive sucrose drinking behavior by more than 2-fold both in male and female mice. These findings suggest that CNS4 penetrates brain tissue and produces pharmacological effects such as those of NMDAR-targeting drugs but with a distinct mechanism, avoiding the undesirable side effects typical of traditional NMDAR blockers. Therefore, CNS4 holds potential as a novel nonopioid analgesic, warranting further investigation. SIGNIFICANCE STATEMENT: N-methyl D-aspartate (NMDA)-subtype glutamate receptors are an attractive target for chronic pain and posttraumatic stress disorder treatments because they play a critical role in forming emotional memories of stressful events. In this translational pharmacology work, we demonstrate the central analgesic and stress-mitigating characteristics of a novel glutamate concentration-biased NMDA receptor modulator, costa NMDA receptor stimulator 4.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103401"},"PeriodicalIF":3.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630343","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":"Antibody immunotherapies for personalized opioid addiction treatment.","authors":"Eric H Rosenn, Miriam Korlansky, Shahin Benyaminpour, Violet Munarova, Eryn Fox, Divyash Shah, Andrea Durham, Nicole Less, Giulio Maria Pasinetti","doi":"10.1016/j.jpet.2025.103522","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103522","url":null,"abstract":"<p><p>Approved therapies for managing opioid addiction involve intensive treatment regimens which remain both costly and ineffective. As pharmaceutical interventions have achieved variable success treating substance use disorders (SUD), alternative therapeutics must be considered. Antidrug antibodies induced by vaccination or introduced as monoclonal antibody formulations can neutralize or destroy opioids in circulation before they reach their central nervous system targets or act as enzymes to deactivate opioid receptors, preventing the physiologic and psychoactive effects of the substance. A lack of \"reward\" for those suffering from SUD has been shown to result in cessation of use and promote long-term abstinence. Decreased antibody production costs and the advent of novel gene therapies that stimulate in vivo production of monoclonal antibodies have renewed interest in this strategy. Furthermore, advances in understanding of SUD immunopathogenesis have revealed distinct mechanisms of neuroimmune dysregulation underlying the disorder. Beyond assisting with cessation of drug use, antibody therapies could treat or reverse pathophysiologic hallmarks that contribute to addiction and which could be the cause of chronic cognitive defects resulting from drug use. In this review, we synthesize key current literature regarding the efficacy of immunotherapies in managing opioid addiction and SUD. We will explore the neuropharmacology underlying these treatments by relating evidence from studies on the use of antibody therapeutics to counteract various drug behaviors and by drawing parallels to the similar immunopathology observed in neurodegenerative disorders. Finally, we will discuss the implications of novel immunization technologies and the application of computational methods in developing personalized addiction treatments. SIGNIFICANCE STATEMENT: Significant new evidence contributing to our understanding of substance use disorders has recently emerged leading to a paradigm shift concerning the role of immunology in the neuropathogenesis of opioid use disorder. Concurrently, immunotherapeutic technologies such as antibody therapeutics have advanced the capabilities regarding applications that take advantage of these key principles. This article reviews key antibody-based treatments being studied and highlights directions for further research that may contribute to the management of opioid use disorder.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103522"},"PeriodicalIF":3.1,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143670211","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":"Metabolomic and lipidomic profiling reveals convergent pathways in attention deficit hyperactivity disorder therapeutics: Insights from established and emerging treatments.","authors":"Bartosz Grzymala, Haraldur Þorsteinsson, Dagmar Þöll Halldórsdóttir, Hildur Sóley Sveinsdóttir, Brynja Rún Sævarsdóttir, William H J Norton, Matthew O Parker, Óttar Rolfsson, Karl Ægir Karlsson","doi":"10.1016/j.jpet.2025.103403","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103403","url":null,"abstract":"<p><p>Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with unclear pathological mechanisms. ADHD is treated with both stimulant and nonstimulant medications, but their therapeutic mechanisms and impact on brain metabolites are not fully understood. This study employed an untargeted metabolomics approach with liquid chromatography mass spectrometry to investigate the pathogenesis of ADHD, as well as the effects of established and novel therapeutics. We characterized the metabolomic signatures of the adgrl3.1 mutant zebrafish ADHD model and examined the impact of methylphenidate, guanfacine, atomoxetine, and 5 novel putative therapeutics identified in a prior screen, including amlodipine. Our analysis revealed that the drugs commonly affect pathways related to amino acid and lipid metabolism, specifically involving glycine, serine, threonine, phenylalanine, lysophosphatidylcholine, and sphingomyelin. This convergence on similar metabolic targets was unexpected and suggests a broader, systemic effect of ADHD therapeutics, challenging the traditional view of distinct drug mechanisms. Amlodipine exhibited metabolic effects consistent with established treatments, indicating its potential as a viable alternative or adjunct therapy. These findings provide new insights into the metabolic underpinnings of ADHD and highlight potential targets for developing improved therapeutic strategies. SIGNIFICANCE STATEMENT: This study explores the metabolic pathways affected by attention deficit hyperactivity disorder treatments using a zebrafish adgrl3.1 mutant model. Untargeted metabolomics revealed that both established and novel attention deficit hyperactivity disorder medications influence common amino acid and lipid metabolism pathways, suggesting systemic effects. Notably, amlodipine showed similar impacts as current drugs, offering promise as an alternative therapy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103403"},"PeriodicalIF":3.1,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625060","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":"Predicting the effects of single pathological mutations in hemophilia A and type 2N von Willebrand diseases using AlphaFold2-multimer and AlphaFold3.","authors":"Ziyu Zhang, Heng Zhang, Wen Dai","doi":"10.1016/j.jpet.2025.103402","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103402","url":null,"abstract":"<p><p>Most factor VIII (FVIII) in circulation exists in a complex with von Willebrand factor (vWF). The interaction between FVIII and vWF is vital for normal hemostatic function, and disruptions in this interaction can lead to bleeding disorders such as von Willebrand disease or hemophilia. However, the impact of pathological mutations on the binding between FVIII and vWF remains largely uncharacterized. In the current study, we used AlphaFold2-multimer and AlphaFold3 to predict the complex involving FVIII and vWF. Additionally, we explored how known mutations in FVIII or vWF, which can result in mild to severe forms of hemophilia and type 2N von Willebrand disease, affect this complex. Our predictions confirm that AlphaFold2 and AlphaFold3 can accurately model the FVIII/vWF complex in a manner consistent with existing cryogenic electron microscopy structures. However, the single pathological mutations can generally disrupt the complex interface predicted by AlphaFold2-multimer but not AlphaFold3. Molecular dynamic simulations showed that the flexibility of several common regions was affected by single pathological mutations. We further designed a new FVIII construct using AlphaFold2, which holds promise as a more effective therapeutic agent with reduced autoimmune responses. In summary, our findings suggest that in combination with molecular dynamics, AlphaFold2 is a valuable tool for swiftly assessing the impact of both known and novel mutations on hemophilia, with potential applications in precision medicine and the development of novel therapeutic interventions. SIGNIFICANCE STATEMENT: This study provides novel insights into the protein structure of the factor VIII and von Willebrand factor complex. This research demonstrates that AlphaFold2-multimer rather than AlphaFold3 can better predict the variations in the complex corresponding to clinical observations of disease severity. These findings not only deepen our comprehension of hemostatic mechanisms but also establish AlphaFold2 in combination with molecular dynamics as a useful tool for hemophilia research, with potential applications in precision medicine and the development of novel therapeutic interventions.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103402"},"PeriodicalIF":3.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143604905","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":"γ-Secretase modulation inhibits amyloid plaque formation and growth and stimulates plaque regression in amyloid precursor protein/presenilin-1 mice.","authors":"Gunnar Nordvall, Ping Yan, Lotta Agholme, Johan Lundkvist, Johan Sandin, Henrik Biverstål, Bengt Winblad, Henrik Zetterberg, Rebecka Klintenberg, Mats Ferm, John R Cirrito, Jin-Moo Lee","doi":"10.1016/j.jpet.2025.103400","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103400","url":null,"abstract":"<p><p>γ-Secretase modulators (GSMs) represent an emerging oral therapy for preventing and targeting Aβ-amyloidosis in Alzheimer disease. Aβ is a family of peptides of varying lengths where both the total and relative amounts of the individual Aβ peptides affect the process of amyloidosis. In contrast to inhibitors of Aβ synthesis, GSMs do not affect the total amount of Aβ peptides generated but decrease longer more amyloidogenic Aβ species while increasing the production of shorter less amyloidogenic Aβ peptides. In this study, we investigated how this modulation of Aβ production affects Aβ plaque dynamics in the brains of APP/PS1dE9 transgenic mice. Similar to studies with different inhibitors of Aβ synthesis, we found that 28 days of once-daily oral treatment with the GSM AZ4126 (100 μmol/kg) resulted in a strong reduction in plaque formation and plaque growth. In addition, and in contrast to Aβ production inhibitors, the GSM AZ4126 caused a significant reduction in the size of established Aβ plaques. Moreover, the antiamyloidogenic activity was accompanied by a marked reduction in brain interstitial fluid Aβ40 and Aβ42 and an increase in Aβ37. Treatment of induced pluripotent stem cell-derived cortical neurons with the GSM AZ4126 reduced secreted Aβ40 and Aβ42 dose-dependently and with a complementary increase in Aβ37 and Aβ38. These studies unravel a previously unknown antiamyloidogenic effect of GSMs, suggesting that they promote the clearance of already established Aβ pathology in addition to their inhibition of Aβ amyloid formation. SIGNIFICANCE STATEMENT: Immunotherapies promoting Aβ-amyloid clearance have shown efficacy in early Alzheimer disease, but complementary Aβ targeting therapeutic approaches are needed. γ-Secretase modulators (GSMs) target Aβ production with an effective and tolerable mechanism. This study demonstrates that a GSM not only inhibits Aβ-amyloid formation but also promotes Aβ-plaque clearance in experiments conducted in an Aβ-amyloidosis mouse model and supports further development of GSMs as an effective oral treatment for Alzheimer disease.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103400"},"PeriodicalIF":3.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584829","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":"Managing thrombus formation with EL2-5HTVac: A selective vaccination-based approach targeting the platelet serotonin 5-HT_2AR.","authors":"Ahmed B Alarabi, Fadi T Khasawneh, Fatima Z Alshbool","doi":"10.1016/j.jpet.2025.103399","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103399","url":null,"abstract":"<p><p>Cardiovascular disease is the leading global cause of death, largely attributable to thrombotic events that can result in conditions like myocardial infarction and stroke. The serotonin 2A receptor (5-HT_2AR) has been identified as a key mediator in platelet aggregation and thrombogenesis, making it a promising target for antithrombotic therapies. Current 5-HT_2AR antagonists, however, have been limited by nonselectivity and adverse effects. This study introduces a novel vaccine designed to target the ligand-binding domain of 5-HT_2AR, which resides in the second extracellular loop (EL2). This vaccine, referred to as \"EL2-5HTVac,\" is expected to provide a long-lasting and selective therapeutic approach without the complications of increased bleeding risk. In this study, we demonstrate that EL2-5HTVac induces a robust immune response with a significant elevation in EL2-specific antibodies in comparison with the controls. Furthermore, vaccinated mice exhibited prolonged occlusion times in a FeCl₃-induced carotid artery thrombosis model without extending tail bleeding times, indicating a favorable safety profile. The EL2-5HTVac also effectively inhibited the serotonin-induced platelet shape change. Additionally, it also blocked serotonin-enhanced ADP-induced platelet aggregation, suggesting an ability to prevent serotonin-facilitated amplification of platelet activation. These findings suggest that EL2-5HTVac offers a dual advantage of thromboprotection and maintenance of hemostasis, potentially overcoming limitations of existing antithrombotic strategies. Future studies should focus on the long-term efficacy and safety of EL2-5HTVac, as well as the feasibility of a vaccination-based approach in larger animal models for eventual clinical application. SIGNIFICANCE STATEMENT: This study documents the utility of a vaccine as a potential antithrombotic agent. The vaccine can prevent thrombus formation without affecting hemostasis (causing bleeding).</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103399"},"PeriodicalIF":3.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586119","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":"Morphine-induced hyperalgesia impacts small extracellular vesicle microRNA composition and function.","authors":"Deepa Reddy, Zhucheng Lin, Sujay Ramanathan, Xuan Luo, Richa Pande, Yuzhen Tian, Christine M Side, Jacqueline M Barker, Ahmet Sacan, Julie A Blendy, Seena K Ajit","doi":"10.1016/j.jpet.2025.103398","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103398","url":null,"abstract":"<p><p>Morphine and other synthetic opioids are widely prescribed to treat pain. Prolonged morphine exposure can paradoxically enhance pain sensitivity in humans and nociceptive behavior in rodents. To better understand the molecular mechanisms underlying opioid-induced hyperalgesia, we investigated changes in microRNA (miRNA) composition of small extracellular vesicles (sEVs) from the serum of mice after a morphine treatment paradigm that induces hyperalgesia. We observed significant differential expression of 18 miRNAs in sEVs from morphine-treated mice of both sexes compared with controls. Several of these miRNAs were bioinformatically predicted to regulate cyclic AMP response element binding protein (CREB), a well characterized transcription factor implicated in pain and drug addiction. We confirmed the binding and repression of Creb mRNA by miR-155 and miR-10a. We tested if serum-derived sEVs from morphine-treated mice could elicit nociceptive behavior in naïve recipient mice. Intrathecal injection of 1 μg sEVs did not significantly impact basal mechanical and thermal thresholds in naïve recipient mice. However, prophylactic 1 μg sEV administration in recipient mice resulted in faster resolution of complete Freund's adjuvant-induced mechanical and thermal inflammatory hypersensitivity. Other behaviors assayed following administration of these sEVs were not impacted, including sEV-conditioned place preference and locomotor sensitization. These results indicate that morphine regulation of serum sEV composition can contribute to analgesia and suggest a potential for sEVs to be a nonopioid therapeutic intervention strategy to treat pain. SIGNIFICANCE STATEMENT: A mouse model of opioid-induced hyperalgesia was used to show that chronic morphine treatment causes differential microRNA packaging into small extracellular vesicles (sEVs) present in the serum of mice. Two of these sEV microRNAs can downregulate CREB expression, and administration of these sEVs attenuates pain hypersensitivity in recipient mice. These studies position sEVs as a potential pain therapeutic and highlight changes underlying opioid-induced hyperalgesia, shedding light on a phenomenon with unclear pathophysiology.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103398"},"PeriodicalIF":3.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586134","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":"Antagonism of the antinociceptive effects of fentanyl and the veterinary anesthetic xylazine in mice.","authors":"Kerim Cakir, Jumar Etkins, Mariah L Nguyen, Karen Gonzalez, Gabriel Enrique Vivas Casanova, Ellen A Walker","doi":"10.1016/j.jpet.2025.103397","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103397","url":null,"abstract":"<p><p>A recent twist to the ongoing tragedy of the opioid epidemic is the adulteration of fentanyl with the veterinary tranquilizer xylazine, an α₂-adrenoreceptor agonist. Unfortunately, our knowledge of how fentanyl and xylazine interact pharmacologically in different behavioral assays is limited. We examined fentanyl and xylazine alone, with 4 antagonists, and in multiple dose ratio combinations using a 52.5 °C hot-plate antinociception assay in Swiss-Webster male and female mice. Both fentanyl and xylazine produced full, dose-dependent increases in antinociception. In antagonism studies, naltrexone blocked fentanyl whereas yohimbine and the selective α₂-adrenoreceptor antagonist, idazoxan, blocked the antinociceptive effects of xylazine. Naltrexone failed to inhibit xylazine antinociception and yohimbine increased or decreased the potency of fentanyl depending on the dose. Haloperidol, a D2/σ₁ antagonist, significantly shifted the potency of fentanyl and xylazine to the left. Overall, combining xylazine with fentanyl failed to significantly alter the potency of fentanyl although when xylazine proportion was higher, fentanyl was significantly less potent than fentanyl alone. Either naltrexone or yohimbine alone failed to block the 2.5X xylazine to fentanyl combination. However, naltrexone with either yohimbine or idazoxan blocked the antinociceptive effects of the 2.5X xylazine to fentanyl combination suggesting that both opioid and noradrenergic receptors appear involved in the antinociceptive effects of this combination. In conclusion, the antinociceptive effects of fentanyl combined with xylazine are dependent on the proportions coadministered and multiple antagonists may be required to block the effects of fentanyl adulterated with xylazine. SIGNIFICANCE STATEMENT: Combinations of the opioid agonist fentanyl and the veterinary tranquilizer xylazine currently appear on the illicit drug market. The experiments described here examine the pharmacology of these drugs alone and in combination using a model of antinociception in mice to better understand the underlying receptor mechanisms for fentanyl alone, xylazine alone, and fentanyl and xylazine in combination. The antinociceptive effects were predominantly a simple combination of opioid and α₂-adrenoreceptor agonism.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103397"},"PeriodicalIF":3.1,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557185","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":"Exploring new frontiers in the treatment of HIV-associated neurocognitive disorder.","authors":"Barkha J Yadav-Samudrala, Sylvia Fitting","doi":"10.1016/j.jpet.2024.100040","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100040","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100040"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536841","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":"Understanding CXCR2 antagonism with a dynamic allosteric ternary complex model.","authors":"Rui Li, Richard Frisbie, Fabien Vincent, Atli Thorarensen","doi":"10.1016/j.jpet.2024.100049","DOIUrl":"https://doi.org/10.1016/j.jpet.2024.100049","url":null,"abstract":"<p><p>The CXC chemokine receptor 2 (CXCR2) antagonist SB265610 displays different patterns of antagonism using in vitro binding and cell-based assays. In addition, CXCR2 antagonists, although likely sharing a similar allosteric binding mechanism, display different patterns in the same cell-based assays. Furthermore, clinical studies with CXCR2 antagonists had mixed success in demonstrating target modulation and efficacy, despite favorable exposures based on published binding affinities. Herein, we aimed to understand the mechanism leading to these apparent inconsistencies with a dynamic allosteric ternary complex model. The model was applied in analyzing both in vitro data and clinical neutrophil counts data of CXCR2 antagonists. We extended previous hypotheses into a unified hypothesis, which postulates that, although allosteric binding of a CXCR2 antagonist is not affected by the endogenous agonist, the antagonism is surmountable as the antagonist loses its potency with increased concentrations of endogenous agonist because of the hyperbolic relationship between agonist-occupied receptor and biological response (which is possibly a result of receptor reserve). Antagonists with slow binding kinetics are apparently insurmountable, but only under unsteady-state conditions. Dynamic allosteric ternary complex model following this hypothesis can describe both in vitro and clinical data of CXCR2 antagonists. The inconsistent patterns of CXCR2 antagonism are interpreted as potential receptor reserve in cell-based assays with unsteady-state binding for some compounds. Because the binding process likely reaches quasi steady state in clinical trials, the lack of pharmacology effect for some antagonists is due to suboptimal potency rather than fast binding kinetics. This model may be applicable to other receptors to help predict clinical responses of allosteric antagonists. SIGNIFICANCE STATEMENT: Known CXC chemokine receptor 2 (CXCR2) antagonists are allosteric and do not compete with endogenous agonists. However, this antagonism is surmountable in some assays, but not others, and for some antagonists, but not others. This study proposes a unified hypothesis to explain observed inconsistent antagonism patterns and apply a mechanistic model to link in vitro findings with clinical outcomes. This study improves our understanding of the pharmacology of CXCR2 antagonists and facilitates the future discovery of antagonists with similar mechanisms for CXCR2 or other G protein-coupled receptors.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 2","pages":"100049"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537286","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}