British Journal of Pharmacology最新文献

{"title":"IA-0130, a novel 3-(1,3-diarylallylidene)oxindole derivative, alleviates ovarian cancer via inhibiting IL-6/gp130/STAT3 signalling.","authors":"Sun-Ae Park, Hee Jung Kim, Lee Kyung Kim, Hae-Ri Lee, Bo-Kyung Jung, Ji Hyeon Kim, Myung Jin Kim, Tae Gwon Oh, Hee Eun Kang, Kye Jung Shin, Jae Hong Seo, Tae-Hwe Heo","doi":"10.1111/bph.70142","DOIUrl":"https://doi.org/10.1111/bph.70142","url":null,"abstract":"<p><strong>Background and purpose: </strong>Dysregulation of the IL-6/glycoprotein 130(gp130)/STAT3 signalling axis is implicated in several human diseases, particularly cancer. Notably, gp130, a single transducer of this signalling axis, is a target for ovarian cancer treatment. However, data regarding small-molecule inhibitors of gp130 are lacking. Therefore, we aimed to identify a 3-(1,3-diarylallylidene)oxindole derivative that binds gp130 and reveal the anticancer mechanism acting on the IL-6/gp130/STAT3 pathway in ovarian cancer.</p><p><strong>Experimental approach: </strong>We synthesised 24 derivatives based on the scaffold of 3-(1,3-diarylallylidene)oxindole, and derivatives that inhibit IL-6 signalling were selected using HEK-Blue™ IL-6 cells. The binding of derivatives to gp130 was assessed using surface plasmon resonance. IA-0130, with a strong gp130-binding ability, was selected to observe its effect on the migration, invasion, cell cycle arrest and apoptosis of ovarian cancer cells in comparison to bazedoxifene, a known gp130-binding derivative. Additionally, we examined the mechanism underlying the tumour suppressive effect of IA-0130 in vivo.</p><p><strong>Key results: </strong>We found that IA-0130 inhibited gp130/STAT3 phosphorylation in a concentration-dependent manner in ovarian cancer cell line and also in ovarian cancer-resistant cell line. By suppressing the expression of downstream target genes, IA-0130 inhibited cancer cell growth, metastasis, and invasion and induced apoptosis, exhibiting anticancer effects. In a mouse xenograft model of human ovarian cancer, oral administration of IA-0130 significantly delayed tumour growth. Conclusions and Implications IA-0130 inhibits tumour growth, migration and metastasis by inhibiting IL-6/gp130/STAT3 signalling in ovarian cancer by binding gp130. IA-0130 holds therapeutic potential for treating ovarian cancer as well as anticancer drug-resistant ovarian cancer.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of extracellular matrix remodelling via cyclophilin inhibition in human models of alcohol-related liver fibrosis.","authors":"Una Rastovic, Sara Campinoti, Lai Wei, Bruna Almeida, Sergio Francesco Bozzano, Ramin Amiri, Nicola Harris, Omolola Ajayi, Tsin Shue Koay, Caoimhe Kerins, Fiona N Kenny, Ane Zamalloa, Lissette Adofina, Rosa Miquel, Yoh Zen, Parthi Srinivasan, Krishna Menon, Nigel Heaton, Camilla Luni, Eileen Gentleman, Tanya Shaw, Daren Ure, Shilpa Chokshi, Luca Urbani, Elena Palma","doi":"10.1111/bph.70139","DOIUrl":"https://doi.org/10.1111/bph.70139","url":null,"abstract":"<p><strong>Background and purpose: </strong>Chronic liver disease and hepatic fibrosis constitute a threat to global health. Clinical translation of preclinical research has been limited, highlighting an urgent need for novel treatments. Cyclophilin inhibitors have shown beneficial effects in liver disease; however, the underlying mechanism of action and the effect across different aetiologies remain elusive. Here, we investigate the impact of a pan-cyclophilin inhibitor (rencofilstat, RCF) in human models of fibrosis and alcohol-related liver disease.</p><p><strong>Experimental approach: </strong>RCF was tested in human precision-cut liver slices (PCLS) and primary human hepatic stellate cells (HSCs). Fibrosis and cell activation were assessed using transcriptomic and protein analysis. A comprehensive characterisation of changes in extracellular matrix (ECM) biochemical and structural composition was performed in PCLS and HSC-derived matrix using proteomics, imaging and bioinformatic tools to study ECM alignment. PCLS stiffness upon treatment was assessed by atomic force microscopy.</p><p><strong>Key results: </strong>Transcriptomic and proteomic analyses of PCLS revealed a dramatic impact of RCF on ECM organisation and remodelling. Biochemical composition and fibre alignment analysis of the ECM obtained from HSCs showed a reduction in the amount of ECM core proteins and associated enzymes by RCF, reshaping the architecture of matrix fibres without affecting the HSC activation. The disordered matrix detected in RCF-treated HSC cultures reflected a less-stiff ECM, which was confirmed in the PCLS.</p><p><strong>Conclusions and implications: </strong>This work provides evidence for a novel mechanism linking cyclophilins and ECM remodelling in advanced 3D models of liver disease, with potential applications in therapeutic development.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Are we hallucinating or can psychedelic drugs modulate the immune system to control inflammation?","authors":"Omar Qureshi, Jamie Cowley, Ashley Pegg, Alison J Cooper, John Gordon, Catherine A Brady, Antonio Belli, Sam Butterworth, Rachel Upthegrove, Nick Andrews, Nicholas M Barnes","doi":"10.1111/bph.70138","DOIUrl":"https://doi.org/10.1111/bph.70138","url":null,"abstract":"<p><p>Psychedelic drugs that activate 5-HT_2A receptors have been long used for cultural, medicinal and recreational purposes. Interest in psychedelics for treating psychiatric disorders has resurged recently and is well documented; less well recognised are their anti-inflammatory properties. Growing evidence now demonstrates that psychedelics modulate immune responses, including inhibiting pro-inflammatory cytokine release. Furthermore, in vivo studies demonstrate that psychedelics, like (R)-DOI, reduce inflammation in animal models of acute and chronic inflammatory disease such as asthma. Likewise, some clinical studies with psychedelic drugs (e.g. psilocybin) demonstrate an impact upon circulating cytokine levels, supporting a translation from the animal models to the clinical arena. Such data emphasise the promise of therapeutic approaches targeting inflammation. Interestingly, recent research has also uncovered compounds that maintain therapeutic potential without likely causing psychedelic effects. These discoveries suggest that drugs informed by psychedelic drugs, but which do not evoke psychedelic experiences, which we term PIPI drugs (Psychedelic drug Informed but Psychedelic experience Inactive), could offer effective treatments for mental health and inflammation, presenting new avenues for therapeutic development.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular hydrogen protects against sepsis-induced cardiomyopathy through improving Golgi stress-mediated autophagy, inflammation and apoptosis.","authors":"Shuqi Meng, Jianfeng Liu, Yanhua Luo, Yan Fan, Zhiwei Wang, Yu Song, Shuaijie Pei, Xiaofan Huang, Lina Zhao, Keliang Xie","doi":"10.1111/bph.70132","DOIUrl":"https://doi.org/10.1111/bph.70132","url":null,"abstract":"<p><strong>Background and purpose: </strong>Sepsis-induced cardiomyopathy (SIC) is the primary cause of mortality among people with sepsis. Hydrogen (H₂) has a cardioprotective effect in SIC; however, its specific mechanism remains unclear. We thus explored whether 2% H₂ treatment mitigates SIC through inhibiting Golgi stress and investigated the specific molecular pathways underlying this protective effect.</p><p><strong>Experimental approach: </strong>Male C57BL/6J mice were subjected to caecal ligation and puncture (CLP) to establish the sepsis model. We measured the 7-day survival rates, cardiac function, myocardial damage enzymes, and myocardial haematoxylin and eosin (H&E) staining to evaluate the 2% H₂ on SIC. Immunofluorescence and electron microscopy were used to observe the morphological changes in the Golgi apparatus (GA). Additionally, a Golgi stress-specific agonist (Brefeldin A) was administered to observe whether the therapeutic effect of inhalation of 2% H₂ could be reversed. Finally, we examined the indicators of autophagy, inflammation and apoptosis to explore how 2% H₂ affects the downstream mechanisms of Golgi stress.</p><p><strong>Key results: </strong>The 7-day survival rate of mice decreased, cardiac function deteriorated and myocardial damage enzymes increased after CLP. Golgi stress was associated with elevated levels of autophagy, inflammation and apoptosis levels. These levels decreased following the treatment with 2% H₂ inhalation. However, administration of the Golgi stress-specific agonist Brefeldin A reversed the therapeutic effects of 2% H₂.</p><p><strong>Conclusions and implications: </strong>We found that 2% H₂ exerted a protective effect on SIC, and we determined that its mechanism is related to improving Golgi stress-mediated autophagy, inflammation and apoptosis.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Compartmentalisation in cAMP signalling: A phase separation perspective.","authors":"Milda Folkmanaite, Manuela Zaccolo","doi":"10.1111/bph.70145","DOIUrl":"https://doi.org/10.1111/bph.70145","url":null,"abstract":"<p><p>Cells rely on precise spatiotemporal control of signalling pathways to ensure functional specificity. The compartmentalisation of cyclic AMP (cAMP) and protein kinase A (PKA) signalling enables distinct cellular responses within a crowded cytoplasmic space. Traditionally, compartmentalisation has been attributed to PKA anchoring, phosphodiesterase-mediated cAMP degradation, and restricted cAMP diffusion. Emerging evidence suggests that liquid-liquid phase separation (LLPS) can play a significant role in organising cAMP signalling. LLPS has been implicated in receptor clustering, cyclic nucleotide synthesis, effector activation, signal termination, and offers a dynamic mechanism for spatially restricting cAMP activity. Notably, PKA RIα condensates appear to act as cAMP reservoirs, modulating local cAMP availability and phosphodiesterase-mediated degradation. Disrupting LLPS-mediated condensation of cAMP/PKA pathway components has been linked to cancer and neurodegeneration, pointing to physiological relevance. This review explores current evidence of LLPS in cAMP signalling, highlighting implications for signal compartmentalisation and functional specificity.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A procedure to identify persistent and effort-independent individual differences in preference for heroin over rewarding social interaction.","authors":"Ginevra D'Ottavio, Alana Sullivan, Sara Pezza, Maria Chiara Ruano, Jacopo Modoni, Ingrid Reverte, Claudia Marchetti, Soami F Zenoni, Marco Venniro, Michele S Milella, Fernando Boix, Yavin Shaham, Daniele Caprioli","doi":"10.1111/bph.70125","DOIUrl":"https://doi.org/10.1111/bph.70125","url":null,"abstract":"<p><strong>Background and purpose: </strong>In some individuals, opioid use leads to decreased interest in socially relevant rewards. Recent studies showed that after extended-access heroin self-administration, rats strongly prefer social interaction over single unit-dose heroin infusions. We hypothesized that this strong social preference results from access to a suboptimal heroin dose during testing, and individual differences in heroin versus social choice would emerge if rats were given access to their 'preferred' heroin dose.</p><p><strong>Experimental approach: </strong>In Experiment 1, we trained male rats to lever-press for social interaction, followed by heroin self-administration under continuous-access, no-timeout schedule, which promotes burst-patterned heroin taking. We then tested the rats for choice between single-unit heroin dose and 1-min full-contact social interaction, or 5-min heroin-access (sufficient for burst-patterned heroin taking) and 5-min social interaction. In Experiment 2, we extended the 5-min access procedure to female rats and tested heroin versus limited-contact (screen-based) social interaction. We also manipulated response requirements (effort) for heroin.</p><p><strong>Key results: </strong>Rats given a single-unit heroin dose during choice testing, strongly preferred social interaction. In rats given 5-min heroin-access, large individual differences in heroin preference emerged. These differences were independent of sex, social-interaction conditions and effort manipulations. High heroin intake and burst-patterned heroin taking during self-administration, and high heroin seeking during abstinence predicted individual differences in heroin preference.</p><p><strong>Conclusion and implications: </strong>Access to 'preferred' heroin doses during the choice tests leads to stable and effort-independent individual differences in heroin preference. This procedure provides a platform to study mechanisms of resilience and vulnerability to opioid addiction.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-inflammatory effects of physical stimuli: The central role of networks in shaping the future of pharmacological research.","authors":"Veronica Paparozzi, Reyhaneh Hooshmandabbasi, Alessandro Ravoni, Ying Ma, Luigi Manni, Timothy J Koh, Caroline Maake, Tiziana Guarnieri, Darong Lai, Vitalii Zablotskii, Christine Nardini","doi":"10.1111/bph.70129","DOIUrl":"https://doi.org/10.1111/bph.70129","url":null,"abstract":"<p><p>Addressing complexity in the study of life sciences through Systems Biology and Systems Medicine has been transformative, making Systems Pharmacology the next logical step. In this review, we focus on physical stimuli, whose potential in pharmacology has been neglected, despite demonstrated therapeutic properties. To address this overlooked aspect of pharmacology, we aim to (i), highlight how physical stimuli (mechanical, optical, magnetic, electrical) influence inflammation; (ii) identify known overlaps among transduction mechanisms of physical stimuli and highlight the need for deeper understanding of these mechanisms; (iii) promote advanced network approaches as tools to understand this complexity and enhance the potential of anti-inflammatory physical therapies; and (iv), integrate physical stimuli into the mindset of pharmacologists. The overall purpose of this review is to spark questions rather than provide answers, and to drive research in this critically underexplored area.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic microneurotrophins: Neurotrophin receptors for therapeutics of neurodegenerative diseases.","authors":"Ioanna Zota, Theodora Calogeropoulou, Konstantina Chanoumidou, Ioannis Charalampopoulos, Achille Gravanis","doi":"10.1111/bph.70143","DOIUrl":"https://doi.org/10.1111/bph.70143","url":null,"abstract":"<p><p>Neurodegenerative disorders are characterised by the chronic progressive degeneration of specific neuronal subtypes, neuroinflammation, myelin damage and synaptic loss. Despite their growing incidence, advancements in effective treatments remain limited, because of lack of knowledge for the aetiology of the diverse pathophysiology to design systematic therapies. Several studies highlight the role of neurotrophic factors (NTFs) as potential neuroprotective, regenerative therapies for these disorders. Although NTFs hold protective and regenerative potential for chronic neuroinflammatory and neurodegenerative conditions, major hurdles impair their clinical use, such as optimising the dosage of NTFs, minimising the invasiveness of delivery methods, overcoming blood-brain-barrier (BBB) impermeability and managing side effects. In the last two decades our group have synthesised and screened a large chemical library of steroidal analogues of dehydroepiandrosterone (DHEA), an endogenous steroid hormone, for their ability to mimic neurotrophin neuroprotective and neurogenic actions. Interestingly, DHEA was shown to interact with all neurotrophin receptors, acting most probably as an ancestral neurotrophin early in evolution. However, its chronic pharmacological use is questioned by its action as a major precursor of steroidogenesis. This review highlights the findings of numerous preclinical studies on these synthetic, non-toxic, BBB permeable DHEA derivatives, named microneurotrophins (MNTs), deprived of endocrine actions, activators of specific neurotrophin receptors. The multimodal actions of MNTs against neuronal death and activation of microglia, in addition to their beneficial effects in synaptogenesis and neurogenesis, place them as interesting lead molecules in the armamentarium of therapeutics for neurodegeneration.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoflurane and urethane impact neuronal and astroglial metabolic activity differentially in mouse brain: An ex vivo ¹H-[¹³C]-NMR study.","authors":"Sreemantula Arun Kumar, Akila Ramesh, Pooja Gautam, Anant Bahadur Patel","doi":"10.1111/bph.70113","DOIUrl":"https://doi.org/10.1111/bph.70113","url":null,"abstract":"<p><strong>Background and purpose: </strong>Isoflurane and urethane are among the most routinely used anaesthetics to immobilise rodents in functional studies. However, the quantitative significance of their impacts on neuronal and astroglial activity is not very clear. This study evaluated the impacts of isoflurane and urethane on the metabolic activity of glutamatergic neurons, GABAergic neurons and astrocytes in different brain regions.</p><p><strong>Experimental approach: </strong>Male C57BL/6 mice were anaesthetised with either isoflurane (1.5%) or urethane (1.5 g kg^-1, intraperitoneal), and administered [1,6-¹³C₂]glucose or [2-¹³C]acetate intravenously for 10 or 15 min, respectively. The brain metabolism was arrested using Focussed Beam Microwave Irradiation, and the ¹³C labelling of neurometabolites in the brain tissue extracts was measured ex vivo using ¹H-[¹³C]-nuclear magnetic resonance (NMR) spectroscopy.</p><p><strong>Results: </strong>The levels of aspartate and succinate were decreased, while alanine increased in the studied brain regions in mice exposed to isoflurane compared to awake mice. The labelling of Glu_C4/C3, GABA_C2 and Gln_C4 from [2-¹³C]acetate was decreased in the isoflurane group when compared with awake, suggesting that isoflurane suppresses the astroglial metabolic activity, particularly in the subcortical region. There was a severe reduction in the ¹³C labelling of brain amino acids from [1,6-¹³C₂]glucose in all the brain regions in isoflurane and urethane groups of mice, indicating a severe impact of both anaesthetics on the metabolic activity of glutamatergic and GABAergic neurons.</p><p><strong>Conclusions and implications: </strong>These findings demonstrate that isoflurane and urethane differentially reduce excitatory and inhibitory synaptic transmissions in the brain. Notably, isoflurane shifts cerebral metabolism towards anaerobic respiration.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fast-dissociating D₂ antagonist antipsychotic JNJ-37822681 is a neuronal Kv7 channel opener: Potential repurposing for epilepsy treatment.","authors":"Lidia Carotenuto, Oliver Keminer, Giusy Carleo, Andrea Zaliani, Antonio Leo, Rita Citraro, Giovambattista De Sarro, Nina Dirkx, Marcus Kaji, Sarah Weckhuysen, Jeanette Reinshagen, Vincenzo Barrese, Natascia Guida, Carmine Ostacolo, Francesco Miceli, Philip Gribbon, Maurizio Taglialatela","doi":"10.1111/bph.70119","DOIUrl":"https://doi.org/10.1111/bph.70119","url":null,"abstract":"<p><strong>Background and purpose: </strong>Pharmacological activation of neuronal M-current mediated by Kv7 (Kv7.2-5) potassium channels is a validated mechanism for epilepsy treatment. However, since the market withdrawal of the prototype Kv7 activator retigabine, no Kv7 activator is clinically available for this condition. The object was to identify, characterise and validate new neuronal Kv7 channel activators for epilepsy treatment.</p><p><strong>Experimental approach: </strong>A fluorescence-based high-throughput assay was optimised in cells stably expressing Kv7 channels to screen two repurposing libraries including >8000 compounds. Whole-cell patch clamp, in silico docking, mutagenesis and multielectrode array recordings in human induced-pluripotent stem cell (hiPSCs)-derived cortical-like glutamatergic neurons (iNeurons) were used to evaluate compound(s) potency and efficacy, binding site, and effects on neuronal activity, respectively. Finally, anticonvulsant activity was assessed in two acute seizure models in male mice.</p><p><strong>Key results: </strong>JNJ-37822681, a fast-dissociating D₂ receptor antagonist in clinical development as antipsychotic, enhanced Kv7.2-5 currents with potency and efficacy largely comparable to retigabine. In Kv7.2 subunits, JNJ-37822681 binding site largely overlapped that for retigabine. In iNeurons, JNJ-37822681 enhanced the M-current, hyperpolarised the resting membrane potential and reduced spontaneous action potential firing. These effects were blocked by the Kv7 antagonist, XE-991, and were not reproduced by the D₂ antagonist (-)-sulpiride. Finally, JNJ-37822681 showed anticonvulsant activity in two well-validated mouse models of acute seizures.</p><p><strong>Conclusions and implications: </strong>Our study reveals that JNJ-37822681, which lacks retigabine's potential safety issues due to chemical liability and is already confirmed as safe for human use, represents a potential treatment of Kv7-related neuronal hyperexcitability disorders.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}