Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Commentary: Behavior as an important determinant of drug action.","authors":"James E Barrett, Alice M Young, Linda Dykstra","doi":"10.1016/j.jpet.2025.103528","DOIUrl":"10.1016/j.jpet.2025.103528","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103528"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710390","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":"Retraction notice to \"Development of Angiotensin IV Analogs as Hepatocyte Growth Factor/Met Modifiers\" [J Pharmacol Exp Ther 340 (2012) 539-548].","authors":"Leen H Kawas, Alene T McCoy, Brent J Yamamoto, John W Wright, Joseph W Harding","doi":"10.1016/j.jpet.2025.103566","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103566","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103566"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022856","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":"Bazedoxifene plus conjugated estrogen to treat menopausal depression-A pilot study.","authors":"Jayashri Kulkarni, Eveline Mu, Qi Li, Marta Malicka, Emorfia Gavrilidis, Anthony de Castella, Caroline Gurvich","doi":"10.1016/j.jpet.2025.103527","DOIUrl":"10.1016/j.jpet.2025.103527","url":null,"abstract":"<p><p>Gonadal hormone fluctuations in the menopausal transition, particularly the decline in brain estrogen levels, significantly contribute to menopausal depression. Although hormone replacement therapy, known as \"menopause hormone therapy,\" effectively manages physical symptoms, it is not routinely used for mental health disturbances due to limited large-scale clinical trial evidence comparing menopause hormone therapy with standard antidepressants. The recognition of menopausal mental illness as being different to major depressive disorder is currently lacking in research and clinical practice. Furthermore, concerns about the long-term safety of estrogen and progestins have prompted the exploration of alternative hormone therapies. Bazedoxifene, a selective estrogen receptor modulator, in combination with conjugated estrogens, is a newer, safe option for physical menopause symptoms. Our 12-week double-blind, randomized, placebo-controlled pilot study evaluated the effects of this combined hormone therapy on menopausal depression in 37 women. Twenty participants received bazedoxifene plus conjugated estrogen, and 17 received placebo. Results indicated that both groups had a decrease in the standard depression rating scale (Montgomery-Asberg Depression Rating Scale) scores from baseline to week 12. However, the decrease was not significantly different between groups. When we used our specific menopause depression rating scale-the Meno-D-we found that women receiving bazedoxifene plus conjugated estrogen improved significantly more compared with women taking the placebo. This suggests that the combined hormone therapy effectively targets the unique symptoms that constitute menopausal depression. Further research is needed to develop targeted treatments for menopausal depression, which appears to be a different type of depression that responds to hormone therapy. SIGNIFICANCE STATEMENT: This pilot study demonstrates that combined hormone therapy with bazedoxifene plus conjugated estrogen significantly improves symptoms of menopausal depression, a condition distinct from major depressive disorder. These findings highlight the potential of targeted hormone treatments for menopausal mental health, warranting further research to develop effective therapies.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103527"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730684","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":"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":"2025-04-01","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":"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":"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":"2025-04-01","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":"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":"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":"2025-04-01","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":"DBeQ derivative targets vacuolar protein sorting 4 functions in cancer cells and suppresses tumor growth in mice.","authors":"Kevin A Fundora, Yan Zhuang, Kouta Hamamoto, Guifang Wang, Longgui Chen, Tatsuya Hattori, Xinwen Liang, Lei Bao, Venugopal Vangala, Fang Tian, Yoshinori Takahashi, Hong-Gang Wang","doi":"10.1016/j.jpet.2025.103524","DOIUrl":"10.1016/j.jpet.2025.103524","url":null,"abstract":"<p><p>Vacuolar protein sorting 4 (VPS4) is an AAA-ATPase that catalyzes the endosomal sorting complex required for transport-III disassembly, mediating various cellular membrane-remodeling processes including endolysosomal membrane repair and autophagosome closure. Humans have 2 VPS4 paralogs, VPS4A and VPS4B, and the loss of either paralog has been identified in a significant proportion of cancers, rendering them dependent on the remaining paralog for survival. In this study, we explored VPS4 inhibition as an anticancer strategy by investigating the mechanisms of VPS4 inhibition-induced cell death and developing small-molecule compounds that target VPS4 functions. We found that genetic inhibition of VPS4 triggered both caspase-8 (CASP8)-dependent apoptosis and caspase-independent cell death in osteosarcoma cells. We synthesized approximately 100 derivatives of the VPS4 and related AAA-ATPase valosin-containing protein inhibitor DBeQ and screened for their inhibitory effects on VPS4 ATPase activity using the EnzChek phosphate assay and a high-content assay monitoring GFP-CHMP4B puncta formation. In cells, the lead compound 4-107 caused endolysosomal damage, disrupted subsequent membrane repair, inhibited autophagy, and led to the accumulation of the endosomal sorting complex required for transport on membranes. These effects were accompanied by the stabilization of CASP8 on autophagosomal membranes, leading to the induction of CASP8-mediated apoptosis. Notably, the CASP8-mediated cell death induced by 4-107 was further enhanced by the loss of either VPS4 paralog. Moreover, 4-107 exhibited antitumor activity in a syngeneic mouse model of neuroblastoma. Our findings provide an important step for targeting VPS4 in cancer and developing VPS4 inhibitors as a cancer treatment strategy. SIGNIFICANCE STATEMENT: VPS4A and VPS4B, paralogs of the AAA-ATPase VPS4, are critical for cancer cell survival. This study reports that 4-107, a DBeQ derivative, inhibits VPS4 ATPase activity, induces CASP8-mediated apoptosis, and suppresses tumor growth in mice. This study supports the further development of VPS4A/B inhibitors as a promising anticancer treatment strategy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103524"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730685","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":"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":"2025-04-01","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":"Menopause-related changes in vascular signaling by sex hormones.","authors":"Tao Li, Zachary E Thoen, Jessica M Applebaum, Raouf A Khalil","doi":"10.1016/j.jpet.2025.103526","DOIUrl":"10.1016/j.jpet.2025.103526","url":null,"abstract":"<p><p>Cardiovascular disease (CVD), such as hypertension and coronary artery disease, involves pathological changes in vascular signaling, function, and structure. Vascular signaling is regulated by multiple intrinsic and extrinsic factors that influence endothelial cells, vascular smooth muscle, and extracellular matrix. Vascular function is also influenced by environmental factors including diet, exercise, and stress, as well as genetic background, sex differences, and age. CVD is more common in adult men and postmenopausal women than in premenopausal women. Specifically, women during menopausal transition, with declining ovarian function and production of estrogen (E2) and progesterone, show marked increase in the incidence of CVD and associated vascular dysfunction. Mechanistic research suggests that E2 and E2 receptor signaling have beneficial effects on vascular function including vasodilation, decreased blood pressure, and cardiovascular protection. Also, the tangible benefits of E2 supplementation in improving menopausal symptoms have prompted clinical trials of menopausal hormone therapy (MHT) in CVD, but the results have been inconsistent. The inadequate benefits of MHT in CVD could be attributed to the E2 type, dose, formulation, route, timing, and duration as well as menopausal changes in E2/E2 receptor vascular signaling. Other factors that could affect the responsiveness to MHT are the integrated hormonal milieu including gonadotropins, progesterone, and testosterone, vascular health status, preexisting cardiovascular conditions, and menopause-related dysfunction in the renal, gastrointestinal, endocrine, immune, and nervous systems. Further analysis of these factors should enhance our understanding of menopause-related changes in vascular signaling by sex hormones and provide better guidance for management of CVD in postmenopausal women. SIGNIFICANCE STATEMENT: Cardiovascular disease is more common in adult men and postmenopausal women than premenopausal women. Earlier observations of vascular benefits of menopausal hormone therapy did not materialize in randomized clinical trials. Further examination of the cardiovascular effects of sex hormones in different formulations and regimens, and the menopausal changes in vascular signaling would help to adjust the menopausal hormone therapy protocols in order to enhance their effectiveness in reducing the risk and the management of cardiovascular disease in postmenopausal women.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 4","pages":"103526"},"PeriodicalIF":3.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788387","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":"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":"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":"2025-04-01","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}