Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"Enhanced negative modulation of urotensin II on cardiac function and [Ca²⁺]_i regulation in a diabetic rat model: Insights into molecular and cellular mechanisms.","authors":"Xiaowei Zhang, Zhe Chen, Jing Cao, Peng Zhou, Zhi Zhang, Xiaoqiang Sun, Yixi Liu, Tiankai Li, Heng-Jie Cheng, Che Ping Cheng","doi":"10.1016/j.jpet.2025.103594","DOIUrl":"10.1016/j.jpet.2025.103594","url":null,"abstract":"<p><p>The direct cardiac effects of urotensin II (UII) in normal and diabetic subjects remain controversial. The alteration and functional significance of cardiac UII/UII receptor (UT) in diabetes are still unclear. We assessed the hypothesis that in diabetes, the cardiomyocyte UII/UT system is increased. This augmentation is proposed to exacerbate the dysfunctional [Ca²⁺]_i regulation, enhance inhibitions of left ventricle (LV) and myocyte contraction and relaxation, leading to worsening cardiac dysfunction. We compared LV myocyte UII and UT expression, LV and myocyte contractile, [Ca²⁺]_i transient ([Ca²⁺]_iT) and calcium current (I_Ca,L) responses to UII stimulation in male Sprague-Dawley rats (12/group) with streptozotocin-induced diabetes mellitus and controls. We found that UII and UT protein levels were significantly greater in diabetic myocytes than in control myocytes. Compared with control rats, UII (400 pmol/kg, i.p.) administration produced greater decreases in LV contractility of E_ES (diabetes mellitus: 32% vs C: 13%) and M_SW with significantly increased LV time constant relaxation in diabetes. In response to UII (10^-5 M) superfusion, diabetic myocytes had much greater decreases in the velocity of shortening and relengthening accompanied by significantly larger decreases in the peak systolic [Ca²⁺]_iT and I_Ca,L (29% vs 15%). These responses were abolished by pretreatment of diabetic myocytes with urantide, pertussis toxin, or dibutyryl-cAMP, respectively. We conclude that UII has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. In diabetes, cardiac UII/UT is upregulated, enhancing UII-caused negative modulation on cardiac function and [Ca²⁺]_i regulation. This may contribute to the progression of cardiac dysfunction in diabetes and diabetic cardiomyopathy. SIGNIFICANCE STATEMENT: Urotensin II (UII) has direct negative inotropic and lusitropic cardiac effects in both normal and diabetic rats. Compared with normal rats, cardiac UII/UII receptors (UT) were upregulated in diabetic rats, resulting in significantly greater decreases in [Ca²⁺]_iT and I_Ca,L and increased inhibitions of left ventricle and myocyte contraction and relaxation. These effects are coupled with UT and mediated by G_i proteins. These data provide new insights and evidence that upregulation of cardiomyocyte UII/UT may promote the progressive cardiac dysfunction in diabetes and diabetic cardiomyopathy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103594"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127975","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":"Metabolic stress-mediated cell death and autophagy in human lung cancer cells.","authors":"Himani Joshi, Ying Huang, M Saeed Sheikh","doi":"10.1016/j.jpet.2025.103598","DOIUrl":"10.1016/j.jpet.2025.103598","url":null,"abstract":"<p><p>Lung cancer remains one of the major causes of cancer-related mortality. Thus, newer therapeutic approaches are urgently needed. Because cancer is a metabolic disease, lung cancer cells have also rewired their metabolism to gain growth advantage and support survival. Therefore, the use of metabolic stress-inducing agents as a therapeutic strategy for lung cancer is an attractive idea. In this study, we have investigated the anticancer potential of CB-839 and metformin. CB-839, a selective glutaminase-1 inhibitor, creates glutamine-deficient conditions, and metformin is an antidiabetic drug. We report that CB-839 and metformin induce metabolic stress and inhibit growth of human lung cancer cells. Of note, lung cancer cells that harbor mutant K-Ras are more sensitive to these agents compared to cells with wild-type K-Ras status. In the K-Ras mutant cells, these agents induce cell death partly, via death receptor 5 (DR5)-dependent extrinsic pathway. However, in the lung cancer cells harboring wild-type K-Ras, these agents activate autophagy without significant effect on DR5 regulation. Pretreatment of K-Ras wild-type cells with autophagy inhibitor improves the anticancer potential of these agents coupled with activation of DR5-dependent pathway. Our results further show that the growth inhibitory effects of these agents appear to be linked to the mutant K-Ras status because pan-K-Ras inhibitor that inhibits the mutant K-Ras proteins blunted the growth inhibitory effects of these agents in cells harboring mutant K-Ras. Collectively, our results provide valuable new insights into exploiting the metabolic rewiring of lung cancer cells by using metabolic stress-inducing drugs as an important therapeutic approach. SIGNIFICANCE STATEMENT: Anticancer potential of CB-839 and metformin is investigated in lung cancer. These agents induce cell death partly, via death receptor 5-dependent pathway, and a relationship with K-Ras status of lung cancer cells is noted. Lung cancer cells with mutant K-Ras are more sensitive compared to cells with wild-type K-Ras. Autophagy inhibition of K-Ras wild-type cells improves the anticancer potential. This study provides new insights into exploiting the metabolic rewiring of lung cancer cells as an important therapeutic strategy.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103598"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12264549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144248411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioactive phytoconstituent millettone as a potential inhibitor of catechol O-methyltransferase: Implications for neuroprotective therapy in Parkinson's disease.","authors":"Mohammad Khalid, Mohammed H Alqarni, Ahmed I Foudah","doi":"10.1016/j.jpet.2025.103592","DOIUrl":"10.1016/j.jpet.2025.103592","url":null,"abstract":"<p><p>Catechol O-methyltransferase (COMT) is a cation-dependent enzyme essential for the metabolism of catechols, including dopamine, norepinephrine, caffeine, and estrogens. COMT is highly expressed in tissues such as the brain, liver, and erythrocytes, and its elevated levels in dopaminergic neurons are implicated in Parkinson's disease. Considering it as a promising target for drug development against Parkinson's disease, this study employed in silico screening of plant-derived compounds from the IMPPAT 2.0 data base to identify potential COMT inhibitors. Compounds were initially filtered out based on their pharmacokinetic properties and binding affinities. Further screening included ligand-receptor interaction calculations, pan-assay interface compounds filtering, ADMET analysis, and biological activity prediction, followed by stability assessments to select the most promising phytochemicals. Millettone emerged as a top candidate, demonstrating high affinity and specific binding interactions with COMT. Comprehensive evaluations, including all-atom molecular dynamics simulations and essential dynamics analysis, further supported millettone's stability and effectiveness as a potential COMT inhibitor. These findings suggest that millettone is a strong candidate for further experimental studies, with potential application as an anti-Parkinson's therapeutic targeting COMT. SIGNIFICANCE STATEMENT: This study identified a plant-based natural compound, millettone, as a potential catechol O-methyltransferase inhibitor through in silico screening and molecular dynamics simulations. Its strong binding and stability suggest therapeutic potential for Parkinson's disease, warranting further experimental validation.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103592"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086389","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":"Mineralocorticoid and estrogen receptors as sex-dependent modulators of vascular health in aging and obesity.","authors":"Casey G Turner, Karla de Oliveira, Iris Z Jaffe, Jennifer J DuPont","doi":"10.1016/j.jpet.2025.103591","DOIUrl":"10.1016/j.jpet.2025.103591","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) is the leading cause of death in both men and women, but there are sex differences in the timing and mechanisms of disease development. Sex differences particularly influence the development of CVD in the presence of aging and obesity, 2 major risk factors of CVD. The mineralocorticoid and estrogen receptors have been identified as important regulators of vascular function in healthy and disease states. Recent evidence has highlighted interactions between these receptors in the vasculature, and innovations in global and cell-specific knockout mouse models have substantially advanced our understanding of sex-dependent roles of these receptors in vascular health and disease. This review summarizes recent advances in the sex-dependent roles of the mineralocorticoid and estrogen receptors in arterial stiffness and vasomotor dysfunction, 2 early markers of CVD development. These vascular outcomes are examined in the context of aging and obesity, 2 of the most prevalent CVD risk factors. SIGNIFICANCE STATEMENT: Cardiovascular disease (CVD) is the leading cause of death globally for women and men, but there are sex differences in the timing of CVD development across the lifespan and in mechanisms driving disease. This review summarizes sex-specific roles of mineralocorticoid and estrogen receptors in arterial stiffness and vasomotor dysfunction during aging and obesity. Understanding sex-specific mechanisms of CVD is critical to developing precision medicine strategies to prevent and treat CVD in women and men.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103591"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093758","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":"A gut response: Application of human enteroid monolayers to probe the mechanism of the goldenseal-mediated inhibition of metformin intestinal absorption.","authors":"Christopher M Arian, Eimear T O'Mahony, Preston K Manwill, Tyler N Graf, Nicholas H Oberlies, Nadja B Cech, John D Clarke, Jason G Smith, Mary F Paine, Edward J Kelly, Kenneth E Thummel","doi":"10.1016/j.jpet.2025.103597","DOIUrl":"10.1016/j.jpet.2025.103597","url":null,"abstract":"<p><p>Continued growth in global sales of natural products has led to an increased risk of natural product-drug interactions that can compromise drug efficacy and safety. One such natural product, goldenseal, was shown to decrease systemic exposure to a subtherapeutic dose of oral metformin in healthy adults. A follow-up study involving therapeutic metformin doses and adults with type II diabetes demonstrated a metformin dose-dependent pharmacokinetic interaction with goldenseal. These results, along with no change in metformin half-life or renal clearance in both studies, suggested that the goldenseal-metformin interaction occurred in the gut via inhibition of an unidentified saturable intestinal transport process. We used enteroid monolayers derived from the duodenum of 4 healthy human adult donors to recapitulate the goldenseal-metformin interaction in vitro and identify the transporters involved in the observed in vivo interaction. Our results implicate thiamine transporter (ThTr) 2 as the predominant transporter involved in metformin uptake through the apical membrane, accounting for approximately 45% of total metformin intracellular accumulation. Additionally, goldenseal inhibited ThTr-2, but only under subsaturating metformin dosing concentrations. The goldenseal-metformin interaction mediated under therapeutic metformin dose conditions involves a low-affinity basolateral transporter, ThTr-1, which accounts for approximately 50% of inhibitable metformin apical to basolateral flux. However, a substantial fraction of metformin flux appears to involve paracellular transport. These results further elucidate the mechanism underlying the goldenseal-metformin interaction and suggest that enteroid monolayers are a promising model to study intestinal natural product-drug interactions. SIGNIFICANCE STATEMENT: The research presented in this article demonstrates the utility of enteroid monolayers to predict and ascertain the mechanisms of drug-drug and natural product-drug interactions. Using this model, the study was able to identify the transporters (thiamine transporter-1 and thiamine transporter-2) involved in metformin absorption that are inhibited by the natural product, goldenseal, which were previously unidentified.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103597"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127924","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":"Hesperidin improves cardiac fibrosis induced by β-adrenergic activation through modulation of gut microbiota.","authors":"Xia Liu, Weiwei Ju, Erjiao Qiang, Dongning Li, Qing Liang, Meina Guo, Weijing Yun, Zhenzhen Chen","doi":"10.1016/j.jpet.2025.103578","DOIUrl":"10.1016/j.jpet.2025.103578","url":null,"abstract":"<p><p>Cardiac fibrosis is a prevalent characteristic of various cardiovascular diseases and poses a significant global health challenge. Recent research has established a robust correlation between gut microbiota and cardiovascular diseases. Hesperidin has been shown to possess cardioprotective properties to some extent. Furthermore, studies suggest that hesperidin may enhance overall health by regulating intestinal flora. However, there is a lack of reports regarding the effects of hesperidin on cardiac fibrosis. This study aimed to investigate the mechanisms by which hesperidin ameliorates cardiac fibrosis through the regulation of gut microbiota and associated metabolites. Cardiac fibrosis was induced in C57BL/6 mice via subcutaneous injection of isoproterenol (5 mg/kg per day) for a duration of 7 days. Echocardiography was used to assess cardiac function, while Masson staining, western blot analysis, and real-time polymerase chain reaction were used to evaluate fibrosis-related indicators. Changes in gut microbiota were analyzed through 16S ribosomal RNA gene sequencing. Our findings indicate that hesperidin significantly mitigates cardiac fibrosis in mice. These beneficial effects are associated with improvements in the dysbiosis of intestinal microbiota observed in fibrotic mouse models. The involvement of gut microbiota in cardiac fibrosis was further corroborated by administering hesperidin therapy to mice depleted of gut microbiota. To our knowledge, this study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis. The use of traditional Chinese medicine to modulate gut microbiota presents a promising strategy for the treatment of cardiac fibrosis. SIGNIFICANCE STATEMENT: The work is extremely interesting because it acts on a frontier of science that relates the influence of the intestinal microbiota with human physiological systems and associated pathologies. This study provides the first evidence that the modulation of gut microbiota by hesperidin contributes to improved outcomes in cardiac fibrosis.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103578"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086391","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":"ProSAAS neuropeptides and receptors GPR171 and GPR83: Potential therapeutic applications for pain, anxiety, and body weight regulation.","authors":"Lloyd D Fricker, Amanda K Fakira, Erin N Bobeck, Megan Raddatz, Kelly Kim, Kayla D DeSchepper, Daniel J Morgan","doi":"10.1016/j.jpet.2025.103599","DOIUrl":"10.1016/j.jpet.2025.103599","url":null,"abstract":"<p><p>Peptides derived from the precursor named proSAAS are some of the most abundant peptides present in the brain, with levels comparable to enkephalin, neuropeptide Y, and several other well-studied neuropeptides. Despite their abundance, the proSAAS-derived peptides are not well-known by the scientific community. In the ∼25 years since their discovery, much has been learned about the role of several of these peptides and their receptors, with functions including energy balance and body weight regulation, fear, anxiety, reward behavior, and pain. This review provides an overview of this emerging field and outlines important areas for further studies. SIGNIFICANCE STATEMENT: Neuropeptides perform important roles in cellular signaling and their receptors are the targets of hundreds of distinct pharmacotherapies. The peptides derived from proSAAS are highly abundant and broadly expressed in the brain, and their receptors represent an emerging target for novel therapeutics.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103599"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199444","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":"Better together? Individual and synergistic effects of noneuphorigenic cannabinoids on visceral sensation.","authors":"Matthew D Coates, Wesley M Raup-Konsavage, Kent E Vrana","doi":"10.1016/j.jpet.2025.103593","DOIUrl":"10.1016/j.jpet.2025.103593","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 6","pages":"103593"},"PeriodicalIF":3.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127925","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":"Modulating hormonally upregulated neu-associated kinase (HUNK) activity in breast cancer: The development of HUNK inhibitors.","authors":"Alexander E Kritikos, Anslyn C Freije, Elizabeth S Yeh","doi":"10.1016/j.jpet.2025.103604","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103604","url":null,"abstract":"<p><p>Hormonally upregulated neu-associated kinase (HUNK) is a serine/threonine protein kinase in the sucrose non-fermenting 1/AMP-activated protein kinase family that promotes cell survival and plays an important role in breast cancer growth and metastasis. Robust methods to alter HUNK expression and activity are currently in use to advance our understanding of this kinase and its function. However, despite its role in the aggressive triple-negative cancer and human epidermal growth factor receptor 2 (HER2)+ breast cancer subtypes, targeted pharmacological inhibition of HUNK is still in its infancy. There are 2 goals of this review: first, to summarize the work done to modulate HUNK activity and advance scientific understanding of the kinase, and second, to describe the current work toward HUNK's pharmacological inhibition and the application of HUNK inhibitors. Clinically, HER2+ breast cancer often develops resistance to the HER2-targeted standard of care therapy, and experimental studies have shown that this can occur via a HUNK-dependent mechanism. In triple-negative breast cancer, where targeted treatments are lacking, HUNK has been shown to promote cancer progression to metastasis. Thus, further research on HUNK and its pharmacology may lead to novel therapeutics for patients with breast cancer and improved treatment outcomes. SIGNIFICANCE STATEMENT: Having recently been identified to promote aggressive breast cancers, hormonally upregulated neu-associated kinase is showing promise as a potential therapeutic target, yet drug discovery in this area is still at an early stage. This review aims to highlight recent efforts and methods to study the kinase and to identify novel inhibitors that may prove useful in continued basic science and translational research.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103604"},"PeriodicalIF":3.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181604","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":"Locomotor and discriminative stimulus effects of fluorinated analogs of amphetamine and methamphetamine in mice and rats.","authors":"Olivia Anchondo, Ritu A Shetty, Michael B Gatch","doi":"10.1016/j.jpet.2025.103617","DOIUrl":"https://doi.org/10.1016/j.jpet.2025.103617","url":null,"abstract":"<p><p>The prevalence of fluorinated amphetamine and methamphetamine analogs on the illicit market has continued to increase in the past decade. The perceived ability of these compounds to bypass legal regulation has resulted in an increasing popularity among drug users; however, their use produces significant adverse effects, including heart failure, cerebral hemorrhage, and death. This study aimed to investigate the effects of phenyl ring fluorination on the abuse potential of 5 synthetic stimulant compounds: 2- and 3-fluoroamphetamine (FA) and 2-, 3-, and 4-fluoromethamphetamine (FMA). The open-field assay was used to observe the locomotor effects of the compounds and to evaluate effective dose ranges and time courses for psychoactive effects in male Swiss-Webster mice. Discriminative stimulus effects were evaluated using male Sprague-Dawley rats trained to discriminate methamphetamine from saline using an fixed-ratio 10 food-maintained reinforcement schedule in a 2-lever operant box. The compounds tested all resulted in time- and dose-dependent stimulation of locomotor activity. Potencies (ED₅₀) ranged from 0.38 to 7.38 mg/kg, with rank-order potency of 2-FMA > methamphetamine > 3-FMA = 3-FA = 2-FMA > 4-FMA. Peak effects varied, with 2-FA, 3-FA, and 3-FMA showing peak effects similar to methamphetamine (5905-7758 counts), while 2-FMA and 4-FMA were weak stimulants with lower peak effects (2200-3980 counts). All fluorinated compounds elicited dose-dependent full substitution for methamphetamine with comparable potencies (ED₅₀ values = 0.32-0.71 mg/kg). The present study indicates that these analogs may have a potential for abuse comparable to that of methamphetamine, although self-administration studies need to be conducted to confirm this, and the locomotor activity data highlight possible mechanistic differences between the positional analogs through the contrasting potencies and efficacies. SIGNIFICANCE STATEMENT: Fluorinated amphetamine analogs have appeared on the illicit market and produce significant adverse effects. The present study shows that these analogs produce methamphetamine-like locomotor stimulant and discriminative stimulus effects and so may have a potential for abuse comparable to that of methamphetamine and other psychostimulants.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":"392 7","pages":"103617"},"PeriodicalIF":3.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484871","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}