Handbook of experimental pharmacology最新文献

{"title":"Biological and Medicinal Aspects of Peptides and Sugar-Based Boron-Containing Compounds.","authors":"Emily L Krinos, Reilly K Gwinn, Webster L Santos","doi":"10.1007/164_2026_852","DOIUrl":"https://doi.org/10.1007/164_2026_852","url":null,"abstract":"<p><p>Boron has proven to be a magic element in synthetic and medicinal chemistry, enabling the development of new chemical reactions and biological activity. The first two boron-containing drugs, bortezomib (BTZ) and ixazomib, are considered dipeptides and have inspired the exploration of other boron-analogs, such as peptide-boron conjugates and novel boron-sugar scaffolds in drug design. Over the years, peptide drugs have enhanced our ability to target enzymes through precise molecular recognition and facilitating protein-drug interactions that are unavailable for small molecules. Sugar-conjugates have added important aspects in drug design by enhancing bioavailability, stability, and targeting tumor cells through sugar receptor interactions. To this end, conjugating boronic acids or esters to therapeutic peptides or sugars can further improve pharmacokinetic and pharmacodynamic properties by initiating reversible covalent binding, improving bioavailability, inducing unique fluorescent properties, and providing alternative uptake mechanisms. Herein, we will discuss the advancements being made in the field of boron medicinal chemistry in terms of boron-containing peptides and sugars, including FDA-approved drugs, chemical biology imaging tools, preclinical compounds, and boron neutron capture therapy (BNCT) delivery agents.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TAAR1 as a Target for Addiction Therapy.","authors":"Samantha M Rios, Shkelzen Shabani, Tamara J Phillips","doi":"10.1007/164_2026_835","DOIUrl":"https://doi.org/10.1007/164_2026_835","url":null,"abstract":"<p><p>The trace amine-associated receptor 1 (TAAR1) has emerged as a target for therapeutic consideration from outcomes in preclinical models of substance use disorders. As an intracellular G protein-coupled receptor prominently expressed within monoaminergic nuclei, TAAR1 acts as a key modulator of biogenic amine transmission. Extensive preclinical studies using selective agonists and genetic models, including knock-out mice and rats, selected mouse lines, recombinant inbred mouse strains, and Taar1 gene-edited mice, demonstrate that TAAR1 activation serves a protective role against addiction-like behaviors. TAAR1 agonists inhibit the rewarding, reinforcing, and reinstatement-inducing effects of multiple drug classes, including amphetamines, cocaine, opioids, and others. Genetic rodent models reveal that a lack of functional TAAR1 elevates vulnerability to voluntary psychostimulant intake and blunts sensitivity to drug-induced aversive and potentially adverse physiological effects. The precise molecular mechanisms underlying these TAAR1-mediated behaviors continue to be explored, involving complex ligand-specific TAAR1 signaling that regulates transporter internalization, neurotransmitter levels, and neuronal activity. Overall, the existing findings support TAAR1 as a therapeutic target for treatment of substance use disorders. However, translating these findings into effective human pharmacotherapies requires navigating ligand-specific effects and pharmacokinetic demands and defining the role of human TAAR1 genetic diversity in therapeutic response.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial Calcium Dysregulation as an Early Trigger of Vascular Dysfunction: Insights into Heavy Metal Toxicity : Heavy Metals and Endothelial Ca²⁺ Dysregulation.","authors":"Romina Cardozo, Luisina Chavarría, Agustín Demarco, Franco Bernech, Rocco Monferrato, Luis Sobrevia, Garth L Nicolson, Gonzalo Ferreira de Mattos","doi":"10.1007/164_2026_817","DOIUrl":"https://doi.org/10.1007/164_2026_817","url":null,"abstract":"<p><p>Endothelial intracellular calcium (Ca²⁺) signaling is a multi-scale control system that couples external stimuli (shear stress, vasoactive agonists, inflammatory mediators) to nitric oxide (NO) production, endothelium-derived hyperpolarization, barrier integrity, angiogenesis, and regulated exocytosis of prothrombotic mediators. Contemporary \"endothelial Ca²⁺ code\" frameworks emphasize that spatially restricted microdomain events, such as TRPV4 \"sparklets,\" IP₃R \"pulsars/wavelets,\" and Piezo1-driven mechanochemical transduction, are decoded into functionally specific outputs, while organellar Ca²⁺ handling from the ER/SR and the mitochondria tunes amplitude, duration, and translation into redox/inflammatory responses. This framework is particularly relevant for toxicology because divalent toxicants can alter not only the magnitude but also the spatial logic of endothelial Ca²⁺ signaling (Moccia et al. 2023).Heavy metals and metalloids, including lead (Pb), cadmium (Cd), mercury (Hg; particularly methylmercury), and inorganic arsenic (As), are increasingly recognized as cardiovascular risk factors capable of perturbing this endothelial Ca²⁺ code early in exposure. Mechanistically, these toxicants (i) impersonate Ca²⁺ or opportunistically bind Ca²⁺-binding motifs, (ii) enter through or modulate Ca²⁺-permeable channels (notably TRP and store-operated pathways), (iii) impair pumps/exchangers or provoke ER stress, and (iv) trigger oxidative stress and inflammatory signaling that reciprocally reshapes Ca²⁺ dynamics and NO bioavailability. The resulting Ca²⁺/redox feed-forward loops can shift the endothelium toward vasoconstriction, permeability, leukocyte adhesion, dysregulated angiogenesis, and thrombosis. Experimental studies of Pb²⁺ cardiotoxicity and Ca²⁺ antagonism, together with broader exposome analyses of Pb and Hg, support the concept that divalent toxicants can act as calcium-mimetic cardiovascular stressors with direct consequences for calcium-dependent signaling (Chavarría et al. 2021; de Mattos et al. 2017; Ferreira et al. 2021a).This review synthesizes endothelial Ca²⁺ physiology; molecular Ca²⁺ handling nodes (channels, pumps, exchangers; ER/SR and mitochondria); evidence that Pb, Hg, Cd, and As disrupt Ca²⁺ homeostasis; downstream dysfunction phenotypes; dose-response and population vulnerability considerations; experimental models and methods; and mitigation strategies and knowledge gaps.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and Tolerability of SGLT2 Inhibitors.","authors":"Marcel H A Muskiet, Daniël H van Raalte, Mark M Smits","doi":"10.1007/164_2026_826","DOIUrl":"10.1007/164_2026_826","url":null,"abstract":"<p><p>The advent of sodium-glucose co-transporter (SGLT) inhibitors - including selective SGLT2 and dual SGLT1/2 agents - has redefined cardiorenometabolic therapy, markedly reducing cardiovascular events, heart failure hospitalizations, and kidney disease progression in patients with and without diabetes. Despite their robust and well-documented benefits, uptake is sometimes limited in specific patient groups, often reflecting concerns about adverse effects. Traditionally reported risks - including hypoglycemia, euglycemic diabetic ketoacidosis, volume depletion, acute kidney injury, genital and urinary tract infections, bone fractures, and lower limb amputations - exhibit heterogeneous clinical relevance; some are not consistently reproduced or are of uncertain clinical significance, whereas others are rare but clinically meaningful and modulated by patient phenotype, comorbidities, and concomitant therapies. Drawing on large cardiovascular and renal outcome trials, supplemented by real-world evidence, which provide estimates of both absolute and relative risks, this chapter offers an evidence-based framework to anticipate, recognize, and mitigate complications, supporting the safe and effective integration of SGLT inhibitors across diverse clinical populations.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGLT2 Inhibitors in Type 1 Diabetes: The Metabolic Perspective.","authors":"Vala Hamidi, Sunder Mudaliar","doi":"10.1007/164_2026_825","DOIUrl":"10.1007/164_2026_825","url":null,"abstract":"<p><p>The introduction of the sodium-glucose cotransporter-2 inhibitors (SGLT2i) was a landmark moment in the treatment of diabetes. Their unique insulin independent mechanism of action, results in decreased reabsorption of glucose at the renal tubular level and increased glucosuria, which lowers blood glucose along with modest weight reduction due to caloric loss in the urine. Today, the SGLT2i are approved not only for their glycemic benefits, but also to reduce the risk of heart failure (HF) hospitalization and progression to chronic kidney disease (CKD) in patients with type 2 diabetes (T2DM) and CKD/HF. Notably, the SGLT2i are also approved for cardiorenal benefits in those without diabetes. However, SGLT2i are not approved for use in those with type 1 diabetes (T1DM) due to the increased risk for diabetic ketoacidosis (DKA) and euglycemic ketoacidosis. This review provides an overview of the various metabolic effects seen with the use of SGLT2i and dual SGLT1/2 inhibitors in patients with T1DM, including beneficial effects on glycemia despite a paradoxical increase in endogenous glucose production (EGP), changes in insulin sensitivity, hyperglucagonemia and changes in substrate oxidation. We also discuss mechanisms leading to increased ketogenesis and a higher risk of DKA in those with T1DM and potential measures to mitigate this risk, so that patients with T1DM can safely avail the robust glycemic and cardiorenal benefits of these agents.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148725062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carboranes as Modulators of Biologically Active Compounds: Case Studies of DNA-Intercalating Agents, Penicillin G and Isoniazid.","authors":"Agnieszka B Olejniczak","doi":"10.1007/164_2026_834","DOIUrl":"10.1007/164_2026_834","url":null,"abstract":"<p><p>Carboranes are boron-rich polyhedral clusters with unique physicochemical properties, including high hydrophobicity, three-dimensional structure, and the ability to act as bioisosteres of aromatic groups. These features make them attractive building blocks in medicinal chemistry. This chapter summarizes recent advances in the design of carborane-containing derivatives of biologically active scaffolds, including 1,8-naphthalimides, acridines, penicillin G, and isoniazid.The incorporation of carborane clusters significantly influenced the biological activity of parent compounds by modulating DNA interactions, anticancer mechanisms, antibacterial activity, lipophilicity, and membrane permeability. In anticancer conjugates, carborane modification affected DNA binding, reactive oxygen species generation, apoptosis induction, and cellular localization. In antibacterial agents, carborane incorporation improved the activity of selected penicillin G and isoniazid derivatives, including activity against resistant bacterial strains.These examples demonstrate that carboranes are versatile pharmacophores capable of enhancing the biological properties of established drug scaffolds and represent promising tools for the development of novel anticancer and antimicrobial agents.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148724275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of SGLT2 Inhibitors in Rodent Models of Diabetic Nephropathy.","authors":"Aqsa Ashfaq, Andrea Pautz, Ebru Arioglu-Inan, Martin C Michel","doi":"10.1007/164_2026_845","DOIUrl":"https://doi.org/10.1007/164_2026_845","url":null,"abstract":"<p><p>Clinical outcome studies have established sodium glucose transporter 2 (SGLT2) inhibitors such as canagliflozin, dapagliflozin, and empagliflozin as nephroprotective agents in diabetic patients. To elucidate underlying mechanisms, a wide range of mouse and rat models of both type 1 and type 2 diabetes (T1DM and T2DM, respectively) have been tested with regard to effects of SGLT2 inhibitors on renal morphology and function in more than 170 studies. T1DM models are largely based on injection of streptozotocin (STZ), whereas T2DM models cover a wider range of models including db/db mice and various combination of high-fat diets plus (low-dose) STZ. While approved only in patients with T2DM, SGLT2 inhibitors lower glucose in models of T1DM and T2DM. Study designs included treatment starting within 7 days of diabetes induction, 1-4 weeks, and more than 4 weeks thereafter. The latter is used most often, probably because it appears to have the greatest translational value. In male rodents, SGLT2 inhibitors improved nephropathy as determined by serum levels of creatinine or blood urea nitrogen, albuminuria, renal fibrosis in general, glomerulosclerosis, and tubulointerstitial fibrosis. They also improved oxidative stress and inflammatory markers. However, most of the available evidence comes from studies in male rodents. In contrast, only 4% of studies report on female animals including two directly comparing outcomes in male and female rodents. Improvements in female animals tended to be weaker or absent for parameters that were consistently improved in male rodents. Whether this is a peculiarity of the rodent studies or a similar situation exists in diabetic patients remains to be tested.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type 2 Diabetes: Chronic Clinical Metabolic Effects of SGLT2 Inhibitors.","authors":"André J Scheen","doi":"10.1007/164_2026_848","DOIUrl":"https://doi.org/10.1007/164_2026_848","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is strongly associated with an increased risk of cardiovascular disease, chronic kidney disease, heart failure, and metabolic dysfunction-associated steatotic liver disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated significant benefits in improving outcomes among patients with T2D who are at risk of these complications. Emerging clinical evidence indicates that these benefits extend beyond glycemic control and are largely independent of baseline glucose levels. SGLT2is exert pleiotropic effects that encompass a wide range of metabolic, hormonal, hemodynamic, biochemical, and anti-inflammatory actions, each potentially contributing to improved clinical outcomes. However, the relative importance of these mechanisms remains debated and likely varies according to the specific complication targeted-whether atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. This comprehensive review aims to provide an updated overview of the major chronic metabolic effects of SGLT2is, with particular emphasis on those mechanisms that may contribute to improved prognosis in individuals with T2D.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Boron-Containing Drug Candidates in Clinical Trials.","authors":"Billy Vuong, Nitesh Sanghai, Muhammad Shaharyar Khan Afridi, Geoffrey K Tranmer","doi":"10.1007/164_2026_833","DOIUrl":"https://doi.org/10.1007/164_2026_833","url":null,"abstract":"<p><p>Boron has emerged as a versatile element in medicinal chemistry because its empty p-orbital enables reversible covalent interactions with biologically important nucleophiles while supporting diverse, tunable molecular architectures. Following approval of bortezomib in 2003, boron-containing therapeutics have expanded beyond proteasome inhibition to infectious disease, inflammation, thrombosis, metabolic and cardiovascular disease, cancer immunotherapy, and boron neutron capture therapy (BNCT). This chapter critically surveys boron-containing candidates that have entered clinical trials, organizing them by scaffold class: boronic acids, borinic acids, benzoxaboroles, cyclic boron heterocycles, and boron clusters. The agents reviewed include borofalan, delanzomib, flovagatran, dutogliptin, talabostat, numidargistat, OATD-02, AN0128, epetraborole, ganfeborole, acoziborole, taniborbactam, xeruborbactam, and sodium borocaptate, as well as the five FDA-approved boroncontaining drugs (bortezomib, ixazomib, crisaborole, tavaborole, vaborbactam). Their mechanisms, pharmacokinetics, clinical efficacy, safety, regulatory status, and development trajectories are compared. Collectively, the clinical evidence illustrates how boron chemistry enables selective target engagement through reversible covalent inhibition, tRNA trapping, β-lactamase blockade, arginase modulation, and isotope-mediated cellular destruction. Particularly notable advances include borofalan-based BNCT for head and neck cancer, single-dose acoziborole for gambiense human African trypanosomiasis, ganfeborole-containing regimens for tuberculosis, and broad-spectrum cyclic boronate β-lactamase inhibitors designed to restore antibiotic activity against multidrug-resistant Gram-negative pathogens. Across programs, most candidates were generally well tolerated, whereas discontinuations frequently reflected inadequate comparative efficacy, commercial competition, funding limitations, or manufacturing requirements rather than intrinsic boron toxicity. The histories of dutogliptin and talabostat further demonstrate that mechanistically distinctive boron compounds may be successfully repositioned after setbacks in their original indications. Together, these findings show that boron's structural versatility, low inherent toxicity, and capacity for precise, often reversible target binding continue to support productive clinical translation. The review also highlights how clinical success depends on matching pharmacology with unmet need, feasible administration, competitive differentiation, and durable development partnerships. Ongoing advances in scaffold design, delivery, combination therapy, and indication selection are expected to broaden the therapeutic impact of boron-containing medicines.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BODIPY and aza-BODIPY Dyes for Theragnostic Applications.","authors":"Sandra M Rojas-Montoya, Mario E Cuevas-Galindo, Mónica Farfán-Paredes, Enrique Ordaz-Romero, Pablo Labra-Vázquez, Rosa Santillan, Norberto Farfán","doi":"10.1007/164_2026_832","DOIUrl":"https://doi.org/10.1007/164_2026_832","url":null,"abstract":"<p><p>BODIPY and aza-BODIPY fluorophores have attracted considerable attention in theragnostic research because of their excellent photophysical properties, high photostability, structural versatility, and ease of chemical functionalization. These characteristics have enabled their application in fluorescence imaging, molecular sensing, photodynamic therapy (PDT), photothermal therapy (PTT), and multifunctional nanoplatforms for diagnosis and treatment. This chapter reviews recent advances in the molecular engineering of BODIPY- and aza-BODIPY-based systems, emphasizing the structural strategies used to modulate their optical properties and therapeutic performance. Particular attention is devoted to the development of activatable probes, photosensitizers, responsive molecular sensors, and nanostructured theragnostic platforms. The discussion highlights how rational molecular design has expanded the biomedical potential of these fluorophores and identifies current challenges and future opportunities for the development of next-generation fluorescent theragnostic agents.</p>","PeriodicalId":12859,"journal":{"name":"Handbook of experimental pharmacology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148678223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}