British Journal of Pharmacology最新文献

{"title":"Rhynchophylline as an agonist of sirtuin 3 ameliorates endothelial dysfunction via antagonizing mitochondrial damage of endothelial progenitor cells.","authors":"Lin Lin, Bowen Sun, Yuanlong Hu, Wenqing Yang, Jie Li, Danyang Wang, Lei Zhang, Mengkai Lu, Yuan Li, Yunlun Li, Dan Zhang, Chao Li","doi":"10.1111/bph.70032","DOIUrl":"https://doi.org/10.1111/bph.70032","url":null,"abstract":"<p><strong>Background and purpose: </strong>Mitochondrial dysregulation of endothelial progenitor cells (EPCs) has been implicated in endothelial destruction and hypertension. Regulation of silent information regulator 3 (sirtuin 3; SIRT3) in mitochondrial damage of EPCs and the underlying molecular mechanisms remain unclear, and evidence of selective SIRT3 agonists for the treatment of hypertension also is lacking.</p><p><strong>Experimental approach: </strong>Here, we discovered a potent SIRT3 agonist, rhynchophylline (Rhy), and explored its underlying action on mitochondrial damage of EPCs and endothelial dysfunction.</p><p><strong>Key results: </strong>In spontaneously hypertensive rats, Rhy reduced blood pressure and ameliorated vasomotion, paralleling improved EPC function in the peripheral circulation. Moreover, Rhy alleviated mitochondrial damage and inhibited apoptosis via the mitochondrial apoptotic pathway. SIRT3 knockdown interrupted the regulation of mitochondrial homeostasis induced by Rhy, thus abolishing its antagonizing effect on EPC dysfunction and endothelial damage, suggesting that Rhy protection of EPC mitochondria is mediated via the activation of SIRT3. Rhy restrained the production of mitochondrial ROS and improved the activity of superoxide dismutase 2 (SOD2) in a SIRT3-dependent manner, whereas silencing SOD2 eliminated the inhibition by Rhy of oxidative stress and apoptosis, reflecting that SOD2 was indispensable for the regulation of Rhy on mitochondrial dysfunction and the mitochondrial-mediated apoptosis pathway.</p><p><strong>Conclusion and implications: </strong>SIRT3-dependent mitochondrial homeostasis contributes to attenuating hypertension-related EPC dysfunction and endothelial injury, and Rhy itself is a potent and targeted SIRT3 agonist that prevented mitochondrial dysfunction by regulating the SIRT3/SOD2 pathway, which may provide new clues for drug candidates for hypertension therapeutics.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751199","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":"GI-Y2, a novel gasdermin D inhibitor, attenuates sepsis-induced myocardial dysfunction by inhibiting gasdermin D-mediated pyroptosis in macrophages.","authors":"Yiling Mei, Xudong Chen, Si Shi, Wante Lin, Zhenfeng Cheng, Xiaoxi Fan, Wenqi Wu, Jibo Han, Weijian Huang, Bozhi Ye, Shanshan Dai","doi":"10.1111/bph.70040","DOIUrl":"https://doi.org/10.1111/bph.70040","url":null,"abstract":"<p><strong>Background and purpose: </strong>Myocardial dysfunction is a significant complication associated with sepsis. However, there are currently no specific and effective treatments available. Inhibiting gasdermin D (GSDMD)-mediated pyroptosis has shown promise in mitigating sepsis-induced myocardial dysfunction. The GSDMD inhibitor Y2 (GI-Y2) has been demonstrated to directly bind to GSDMD. Nonetheless, it remains uncertain whether GI-Y2 offers a cardioprotective effect in the context of sepsis-induced myocardial dysfunction.</p><p><strong>Experimental approach: </strong>A mouse model of sepsis was created using lipopolysaccharide (LPS), caecal ligation and puncture. Following treatment with GI-Y2 or macrophage membrane-encapsulated GI-Y2 nanoparticles (GI-Y2@MM-NPs), myocardial dysfunction and pyroptosis levels in heart tissues were assessed. Transcriptome sequencing revealed the molecular mechanism of GI-Y2 in treating septic cardiomyopathy.</p><p><strong>Key results: </strong>We observed that GI-Y2 alleviated myocardial dysfunction and attenuated cardiac inflammation in mice induced by LPS, caecal ligation and puncture. GI-Y2 reduced macrophage pyroptosis and attenuated macrophage-mediated cardiomyocyte injury induced by LPS/nigericin. Concurrently, we confirmed the protective effect of GI-Y2 against LPS-induced cardiac dysfunction was abolished in the absence of GSDMD. Additionally, GI-Y2 attenuated the mitochondrial damage induced by LPS by inhibiting GSDMD in the mitochondria. Furthermore, we developed GI-Y2@MM-NPs to enhance the targeting capability of GI-Y2 towards macrophages in heart tissues and demonstrated its protective effect in vivo.</p><p><strong>Conclusion and implications: </strong>These findings indicate that GI-Y2 alleviates septic myocardial injury and dysfunction by specifically targeting GSDMD, thereby inhibiting GSDMD-mediated pyroptosis and mitochondrial damage. Both GI-Y2 and GI-Y2@MM-NPs may serve as promising therapeutic options for addressing septic myocardial dysfunction.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751187","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":"Efficacy of IDOR-1117-2520, a novel, orally available CCR6 antagonist in preclinical models of skin dermatitis.","authors":"Paulina Kulig, Pijus Brazauskas, Madeleine Suffiotti, Emilie Raoult, Ulrike Babilonski, Bérengère Renault, Ursula Grieder, Enrico Vezzali, Peter Blattmann, Marianne M Martinic, Mark J Murphy","doi":"10.1111/bph.70025","DOIUrl":"https://doi.org/10.1111/bph.70025","url":null,"abstract":"<p><strong>Background and purpose: </strong>The chemokine receptor CCR6 guides pathogenic T17 cells, implicated in autoimmune diseases including psoriasis, to sites of inflammation via the chemokine CCL20. Therefor, pharmacological inhibition of CCR6⁺ immune cell migration provides a novel therapeutic approach. Translatability of such an intervention has not yet been assessed in detail. We evaluated the translatability of the Aldara® mouse model induced skin inflammation to psoriasis, with particular focus on immune cell trafficking and assessed the efficacy of IDOR-1117-2520, a highly selective, potent and orally available CCR6 small inhibitor.</p><p><strong>Experimental approach: </strong>Effects of IDOR-1117-2520 were investigated in the Aldara® and IL23 mouse models of skin inflammation using flow cytometry, RNA sequencing and transcriptome-based cell type deconvolution approaches to characterise immune cell migration patterns. These results were compared to human psoriasis transcriptomics data.</p><p><strong>Key results: </strong>IDOR-1117-2520 dose dependently reduced infiltration of CCR6⁺ immune cells into inflamed skin, and was equally efficacious as IL-17 and IL-23 inhibition in models of skin inflammation. Pathway analysis showed molecular similarities in the immune response between human psoriasis and the Aldara® mouse model. IL-17/IL-23 pathway genes were expressed in both human psoriasis and the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in both the model and in human psoriasis.</p><p><strong>Conclusion and implications: </strong>IDOR-1117-2520 could provide a promising novel targeted approach to treating psoriasis and, potentially, other autoimmune diseases involving the CCR6/CCL20 axis and the IL-17/IL-23 pathway. IDOR-1117-2520 is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742510","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":"(2R,6R)-hydroxynorketamine prevents opioid abstinence-related negative affect and stress-induced reinstatement in mice.","authors":"Andria Michael, Anna Onisiforou, Polymnia Georgiou, Morfeas Koumas, Chris Powels, Elmar Mammadov, Andrea N Georgiou, Panos Zanos","doi":"10.1111/bph.70018","DOIUrl":"https://doi.org/10.1111/bph.70018","url":null,"abstract":"<p><strong>Background and purpose: </strong>Opioid use disorder (OUD) is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states. Classical antidepressants or the currently prescribed opioid pharmacotherapies have limited efficacy to reverse the negative affect or prevent relapse.</p><p><strong>Experimental approach: </strong>Using mouse models, we investigated the effects of ketamine's metabolite (2R,6R)-hydroxynorketamine (HNK) on reversing conditioning to sub-effective doses of morphine in stress-susceptible mice, preventing conditioned-place aversion and alleviating acute somatic abstinence symptoms in opioid-dependent mice. Additionally, we evaluated its effects on anhedonia, anxiety-like behaviours and cognitive impairment during protracted opioid abstinence, while mechanistic studies examined cortical EEG oscillations and synaptic plasticity markers.</p><p><strong>Key results: </strong>(2R,6R)-HNK reversed conditioning to sub-effective doses of morphine in stress-susceptible mice and prevented conditioned-place aversion and acute somatic abstinence symptoms in opioid-dependent mice. In addition, (2R,6R)-HNK reversed anhedonia, anxiety-like behaviours and cognitive impairment emerging during protracted opioid abstinence plausibly via a restoration of impaired cortical high-frequency EEG oscillations, through a GluN2A-NMDA receptor-dependent mechanism. Notably, (2R,6R)-HNK facilitated the extinction of opioid conditioning, prevented stress-induced reinstatement of opioid-seeking behaviours and reduced the propensity for enhanced morphine self-consumption in mice previously exposed to opioids.</p><p><strong>Conclusions and implications: </strong>These findings emphasize the therapeutic potential of (2R,6R)-HNK, which is currently in Phase II clinical trials, in addressing stress-related opioid responses. Reducing the time and cost required for development of new medications for the treatment of OUDs via drug repurposing is critical due to the opioid crisis we currently face.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742509","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":"Ginsenoside Rh1 mitigates mitochondrial dysfunction induced by myocardial ischaemia through its novel role as a sirtuin 3 activator","authors":"Shuaishuai Gong,&nbsp;Hong Chen,&nbsp;Shuhua Fang,&nbsp;Mengyu Li,&nbsp;Jingui Hu,&nbsp;Yue Li,&nbsp;Boyang Yu,&nbsp;Junping Kou,&nbsp;Fang Li","doi":"10.1111/bph.70022","DOIUrl":"10.1111/bph.70022","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>The sirtuin 3 (SIRT3) signalling pathway is an essential target for various cardiovascular diseases (CVDs), although effective interventions in myocardial ischaemia-induced mitochondrial dysfunction remain to be elucidated. Here, we discovered a potent SIRT3 activator and explored its efficacy and mechanism against mitochondrial dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Molecular docking screened for SIRT3 activators among the 10 more common rare ginsenosides. In vivo, left coronary artery ligation induced myocardial ischaemia injury, followed by echocardiography, histopathology and serum biochemical indicators, in C57BL/6J mice. Expression levels of mitophagy and mitochondrial dynamics-associated proteins were examined by western blot (WB), immunofluorescence (IF) and immunohistochemistry (IHC). In vitro, oxygen–glucose deprivation-induced hypoxic injury in neonatal rat ventricular myocytes, and cell viability and mitochondrial function were investigated. SIRT3 small interference RNA (siRNA) was transfected into cardiomyocytes to validate mitochondrial dynamics and mitophagy mechanism regulated by ginsenoside Rh1.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Rh1 exhibited the strongest binding affinity as an effective activator of SIRT3. Rh1 improved cardiac function and mitigated myocardial ischaemia injury in vivo. Rh1 ameliorated oxidative stress, improved mitochondrial network morphology and mitochondrial respiration function in hypoxia-injured cardiomyocytes. Rh1 bound to SIRT3 and simultaneously up-regulated Foxo3a, facilitating its nuclear translocation and reducing acetylation of Foxo3a. Rh1 markedly promoted mitochondrial fusion, inhibited mitochondrial fission and accelerated mitophagy. SIRT3 siRNA abrogated the regulation of Rh1 on oxidative stress, mitochondrial dynamics and mitophagy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>Rh1 is a novel SIRT3 activator and protects against myocardial ischaemia-induced mitochondrial dysfunction, providing new clues to prevent and treat ischaemic injury-associated CVD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 13","pages":"3017-3035"},"PeriodicalIF":6.8,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728713","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":"Time-varying compartmental models capture hours-scale variation in the elimination kinetics of vancomycin in rats","authors":"Matthew H. McDonough,&nbsp;Julian Gerson,&nbsp;Tod Kippin,&nbsp;Wendy Meiring,&nbsp;Kevin W. Plaxco","doi":"10.1111/bph.70020","DOIUrl":"10.1111/bph.70020","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Pharmacokinetics have traditionally been assessed using concentration measurements with relatively low temporal resolution, such as from blood draws, leading to pharmacokinetic profiles estimated from sparse data, often averaged across subjects. Recent advances in in vivo sensors, however, now enable the collection of hundreds of observations over a few hours in individual subjects. Previous analyses of such data for the antibiotic tobramycin identified significant (several-fold), hours-scale changes in the efficiency with which this renally cleared drug is eliminated in anaesthetised rats. Here, we apply similar analyses to study the pharmacokinetics of another renally cleared drug, the antibiotic vancomycin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We estimate vancomycin pharmacokinetic profiles using previously collected time-dense plasma concentration measurements within six anaesthetised rats. Specifically, we fit standard one- and two-compartment models, as well as time-varying one-compartment models (in which the proportionality relating concentration to elimination rate is time-varying), to these data to investigate if the time-varying models are statistically preferred for describing individual-level vancomycin pharmacokinetics, over standard one- and two-compartment models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>One-compartment models incorporating time-varying elimination proportionalities are statistically preferred over standard one- and two-compartment models for five of our six vancomycin time courses. When the initial impact of the distribution phase is removed from these data, a reciprocally time-varying one-compartment model is preferred over the standard-one compartment model in four of five considered datasets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>These results provide further animal-model evidence that the pharmacokinetics of renally cleared drugs can vary significantly over timescales as short as a few hours.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 13","pages":"2986-2996"},"PeriodicalIF":6.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728717","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":"Behavioural and pharmacokinetic analysis of heroin and cocaine self-administration: Effects of timeout on self-administration and choice in male rats","authors":"Ginevra D'Ottavio,&nbsp;Sara Pezza,&nbsp;Jacopo Modoni,&nbsp;Ingrid Reverte,&nbsp;Claudia Marchetti,&nbsp;Soami F. Zenoni,&nbsp;Silvana De Pirro,&nbsp;Daniela Maftei,&nbsp;Roberta Lattanzi,&nbsp;Giuseppe Esposito,&nbsp;Davide Ragozzino,&nbsp;Emiliano Merlo,&nbsp;Marco Venniro,&nbsp;Roberto Ciccocioppo,&nbsp;Fabio Fumagalli,&nbsp;Michele S. Milella,&nbsp;Aldo Badiani,&nbsp;Fernando Boix,&nbsp;Daniele Caprioli","doi":"10.1111/bph.70023","DOIUrl":"10.1111/bph.70023","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Heroin and cocaine users tailor their dosage, frequency and administration route to maximise the drugs' effects or prevent withdrawal symptoms. Counterintuitively, preclinical self-administration and choice experiments employ, almost invariably and regardless of the pharmacokinetic properties of the drug under examination, fixed unit-doses and timeouts (after unit-doses) largely resulting in uniform drug-taking patterns. This uniformity contrasts with the large variability observed in humans, which serves as critical indicator of addiction severity and treatment success. Here, by combining behavioural and pharmacokinetics assessments, we revealed that drug self-administration procedures without timeouts may overcome this limitation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>We analysed heroin- and cocaine-taking patterns and seeking and estimated drug-brain levels in the presence or absence of timeout under different training conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>Removing timeouts had a profound effect on heroin-taking patterns and seeking, promoting the emergence of burst-like intake, yielding higher brain peak concentrations of heroin. In contrast, the removal of timeout had marginal impact on cocaine-taking patterns and seeking.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion and Implications</h3>\u0000 \u0000 <p>The removal of timeout during self-administration revealed distinct cocaine and heroin patterns, with the latter closely resembling human heroin use patterns.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 13","pages":"2968-2985"},"PeriodicalIF":6.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ESG-1-60 and ESG-1-61: Novel dopamine D3 receptor-preferring partial agonists/antagonists that inhibit cocaine taking and seeking in rodents","authors":"Omar Soler-Cedeño,&nbsp;Bradley M. Keegan,&nbsp;Hannah Alton,&nbsp;Guo-Hua Bi,&nbsp;Emily Linz,&nbsp;Caleb D. Vogt,&nbsp;Emma S. Gogarnoiu,&nbsp;Lei Shi,&nbsp;Amy Hauck Newman,&nbsp;Zheng-Xiong Xi","doi":"10.1111/bph.70021","DOIUrl":"10.1111/bph.70021","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Preclinical studies suggest that highly selective dopamine D₃ receptor (D₃R) antagonists or partial agonists hold promise for treating substance use disorders. However, their limited effectiveness in reducing cocaine self-administration is a major drawback. This study investigated whether cariprazine (D₃ receptor-preferring partial agonist) and its analogues ESG-1-60 and ESG-1-61 have enhanced efficacy in reducing cocaine-taking and cocaine-seeking behaviour.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>In vitro BRET experiments were used to characterize the functional efficacies of cariprazine and its analogues. Intravenous cocaine self-administration and reinstatement models were used to evaluate efficacy in reducing cocaine-taking and cocaine-seeking behaviour. Optical intracranial self-stimulation (oICSS) procedures assessed effects on dopamine-dependent behaviour. Open-field locomotion, oral sucrose self-administration and conditioned place-preference were used to evaluate potential unwanted side effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>BRET functional assays indicated that cariprazine and ESG-1-60 are D₃ receptor-preferring partial agonists, while ESG-1-61 is a D₃ receptor-preferring antagonist/inverse agonist. All three compounds inhibited cocaine self-administration under both fixed-ratio and progressive-ratio reinforcement schedules and reduced cocaine-induced reinstatement of drug-seeking behaviour in both male and female rats. The compounds did not alter locomotor behaviour but suppressed sucrose intake and dopamine-dependent oICSS. Cariprazine and ESG-1-61 produced significant place aversion, while ESG-1-60 did not. Chronic administration of ESG-1-60 inhibited cocaine self-administration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Novel D₃ receptor-preferring compounds ESG-1-60 and ESG-1-61 were highly effective in reducing cocaine-taking and cocaine-seeking, under various reinforcement conditions. ESG-1-60 warrants further investigation as a new pharmacotherapy for treating cocaine use disorder as it is effective in these models and lacks unwanted behavioural effects.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 13","pages":"2997-3016"},"PeriodicalIF":6.8,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EXPRESSION OF CONCERN: H2S-Donating Sildenafil (ACS6) Inhibits Superoxide Formation and gp91phox Expression in Arterial Endothelial Cells: Role of Protein Kinases A and G","authors":"","doi":"10.1111/bph.70041","DOIUrl":"10.1111/bph.70041","url":null,"abstract":"<p><b>EXPRESSION OF CONCERN</b>: S. Muzaffar, J. Y. Jeremy, A. Sparatore, P. Del Soldato, G. D. Angelini, and N. Shukla, “H₂S-Donating Sildenafil (ACS6) Inhibits Superoxide Formation and gp91^phox Expression in Arterial Endothelial Cells: Role of Protein Kinases A and G,” <i>British Journal of Pharmacology</i> 155, no. 7 (2008): 984–994, https://doi.org/10.1038/bjp.2008.326.</p><p>This Expression of Concern is for the above article, published online on 29 January 2009 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley &amp; Sons Ltd.</p><p>The Expression of Concern has been agreed following an investigation by the journal after publication of concerns regarding the similarity of a blot in Figure 8 with one published elsewhere, and regarding the underlying data that it represents. The authors were unable to provide a satisfactory explanation and could not provide the original data given the time that had elapsed. However, the journal is issuing this Expression of Concern because the concerns regarding the integrity of the data and the results presented cannot be resolved.</p><p>Author G. D. A. agreed to this Expression of Concern.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 10","pages":"2332"},"PeriodicalIF":6.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EXPRESSION OF CONCERN: Superoxide from NADPH Oxidase Upregulates Type 5 Phosphodiesterase in Human Vascular Smooth Muscle Cells: Inhibition with Iloprost and NONOate","authors":"","doi":"10.1111/bph.70042","DOIUrl":"10.1111/bph.70042","url":null,"abstract":"<p><b>EXPRESSION OF CONCERN</b>: S. Muzaffar, N. Shukla, M. Bond, G. B. Sala-Newby, A. C. Newby, G. D. Angelini, and J. Y. Jeremy, “Superoxide from NADPH Oxidase Upregulates Type 5 Phosphodiesterase in Human Vascular Smooth Muscle Cells: Inhibition with Iloprost and NONOate,” <i>British Journal of Pharmacology</i> 155, no. 6 (2008): 847–856, https://doi.org/10.1038/bjp.2008.300.</p><p>This Expression of Concern is for the above article, published online on 29 January 2009 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by the journal Editor-in-Chief, Péter Ferdinandy; the British Pharmacological Society; and John Wiley &amp; Sons Ltd.</p><p>The Expression of Concern has been agreed due to concerns raised by a third party after publication regarding the similarity of certain blots in Figures 4, 5 and 8 with blots published elsewhere, and regarding the underlying data that they represent. The authors were unable to provide a satisfactory explanation and could not provide the original data given the time that had elapsed. However, the journal is issuing this Expression of Concern because the concerns regarding the integrity of the data and the results presented cannot be resolved.</p><p>Authors M. B., A. C. N., and G. D. A. agreed to this Expression of Concern.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":"182 10","pages":"2333"},"PeriodicalIF":6.8,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bph.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}