Pharmacological Reviews最新文献

{"title":"Total-body positron emission tomography imaging to accelerate radiotracer discovery pipelines.","authors":"Andrew Sutherland, Marc R Dweck, David E Newby, Adriana A S Tavares","doi":"10.1016/j.pharmr.2025.100066","DOIUrl":"10.1016/j.pharmr.2025.100066","url":null,"abstract":"<p><p>The development of the first total-body positron emission tomography (PET) clinical scanner is a transformational moment in nuclear medicine, reigniting the field by tackling 2 long-standing and critical barriers to the widespread clinical use of PET: radiation dose and patient throughput. Total-body PET also provides several other unique research and clinical opportunities, including potential to streamline radiotracer discovery and development pipelines. PET does not exist without radiotracers. However, despite decades of radiotracer development programs, the number of successful PET radiotracers adopted and approved for human use is extremely low. In neurology, an important area for nuclear medicine, only approximately 4% of all novel radiotracers that survive the radiotracer translational \"valley of death\" are adopted clinically. The potential for total-body PET technology to reverse these low numbers of radiotracer development and adoption is high. This will require the PET community to come together with the regulators to chart new frameworks for radiotracer development and translational pipelines. This article will discuss which stages of the radiotracer discovery pipeline can benefit most from the recent development of total-body PET technology. It will review the latest key developments in radiochemistry modernization and describe how these could ameliorate regulatory hurdles and deliver the groundbreaking potential of total-body PET. Finally, this article will highlight emerging radiotracer discovery opportunities that could be rapidly facilitated by total-body PET. SIGNIFICANCE STATEMENT: In addition to creating new opportunities for clinical research and patient care, total-body positron emission tomography technology can also embolden radiochemistry modernization in the clinic and break long-standing translational barriers encountered during radiotracer discovery pipelines.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100066"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblasts-The emerging therapeutic target of the cardiovascular system?","authors":"Sebastiaan E J Asselberghs, Maurice Halder, Rafael Kramann, Judith C Sluimer","doi":"10.1016/j.pharmr.2025.100072","DOIUrl":"10.1016/j.pharmr.2025.100072","url":null,"abstract":"<p><p>Recent advances in single-cell RNA sequencing have uncovered fibroblasts' heterogeneous and plastic nature across the cardiovascular system, highlighting their diverse roles beyond extracellular matrix production, including inflammatory signaling and phenotypic switching. This review synthesizes insights into fibroblast heterogeneity and modulation in healthy and diseased heart and vasculature states. It emphasizes the lack of a consensus nomenclature for fibroblast subtypes, attributing this gap to the need for large-scale meta-analyses and extensive validation studies. The emerging understanding of fibroblast subpopulations and their shared markers across cardiac and vascular tissues introduces therapeutic potential and safety concerns. Although preclinical studies targeting fibroblasts in the heart using gene silencing, editing, or epigenetic modulation show promise, comparable vascular interventions remain limited. Therapeutic strategies could benefit from improved fibroblast-specific markers to minimize off-target effects and enhance precision. Ultimately, the review advocates for refined characterization and nomenclature of fibroblast subsets to better exploit their therapeutic potential, while acknowledging the challenges posed by their overlapping phenotypes and diverse functionalities within the cardiovascular system. SIGNIFICANCE STATEMENT: Fibroblasts are a heterogeneous cell type with critical roles in cardiovascular homeostasis and disease. We explore advances in understanding fibroblast diversity and therapeutic potential. We underscore the importance of precision in cardiovascular disease through a consensus on nomenclature and marker specificity.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100072"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Union of Basic and Clinical Pharmacology. CXX. γ-Hydroxybutyrate protein targets in the mammalian brain-beyond classic receptors.","authors":"Petrine Wellendorph, Stine Juul Gauger, Jens Velde Andersen, Birgitte Rahbek Kornum, Sara M O Solbak, Bente Frølund","doi":"10.1016/j.pharmr.2025.100064","DOIUrl":"10.1016/j.pharmr.2025.100064","url":null,"abstract":"<p><p>γ-Hydroxybutyrate (GHB) is a multifaceted compound with an intriguing, yet undeciphered, pharmacology in the mammalian brain. As a metabolite of GABA it is tightly regulated in terms of synthesis and degradation, and is found in micromolar concentrations in the brain. When GHB is taken in high pharmacological doses, it causes euphoria, relaxation, hypothermia, and sedation, and regulates sleep. Through careful pharmacological and genetic studies, this profile has been convincingly matched to the metabotropic GABA_B receptor where GHB is a weak agonist. These effects explain the illicit substance use of GHB, but also its clinically useful effects as a drug in alcoholism and narcolepsy. Additionally, GHB binds with high affinity to a discrete binding site with high expression in the forebrain, and with very well defined anatomical, biochemical, and pharmacological characteristics. Despite this clear profile, the molecular identity of this binding protein or alleged \"GHB receptor\" has remained uncertain. However, recently, prompted by the development of GHB analogs with low nanomolar affinity and selectivity for the high-affinity site, the target was revealed to be the Ca²⁺/calmodulin (CaM)-dependent protein kinase II alpha subunit-a highly important brain kinase, mediating both physiological processes in synaptic plasticity, and detrimental Ca²⁺ signaling and cell death in cases of brain ischemia. The discovery of calmodulin-dependent protein kinase II alpha subunit as the high-affinity brain target for GHB represents a major leap forward in our understanding of GHB neurobiology, and dictates new times for GHB research, suggesting a potential role for GHB and GHB analogs as integrators of inhibitory and excitatory brain signaling. SIGNIFICANCE STATEMENT: γ-Hydroxybutyrate is a molecule with a multitude of actions in the mammalian brain, and with a rather complex molecular pharmacology. A low affinity at GABA_B receptors, located mainly at inhibitory synapses, and a high affinity at the Ca2+/CaM-dependent protein kinase II alpha subunit, located at excitatory synapses, makes GHB pharmacology especially intriguing.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100064"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative therapeutics for renoprotection: Where we are.","authors":"Monica Cortinovis, Norberto Perico, Giuseppe Remuzzi","doi":"10.1016/j.pharmr.2025.100060","DOIUrl":"10.1016/j.pharmr.2025.100060","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) has become highly prevalent worldwide, with major implications for public health, including increased risk of progression to kidney failure, cardiovascular events, and mortality. Up to a decade ago, renin-angiotensin system inhibitors, that is angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, were the only available pharmacological interventions to slow kidney function loss and limit the associated cardiovascular morbidity and mortality in this context. More recently, landmark trials have demonstrated the ability of novel therapeutics to significantly ameliorate kidney and cardiovascular outcomes in patients with CKD, when added on top of optimized renin-angiotensin system blockade. These include sodium-glucose cotransporter-2 inhibitors in patients with diabetic and nondiabetic kidney disease, as well as the nonsteroidal mineralcorticoid receptor antagonist finerenone and the glucagon-like peptide-1 receptor agonist semaglutide in patients with diabetic kidney disease. We herein review the evolving scenario and the latest evidence for the treatment of CKD, mainly focusing on proteinuric CKD. We started with a presentation of established and more recently approved classes of kidney protective drugs, followed by a discussion of therapeutic interventions under clinical investigation to slow CKD progression. Finally, we underscore the added value of personalized and multidrug interventions, which are becoming increasingly more feasible with the availability of a growing number of kidney protective agents, and are likely to stand as the most powerful tools to safely slow, or even prevent, the progression of proteinuric CKD. SIGNIFICANCE STATEMENT: Chronic kidney disease (CKD) is highly prevalent globally, and is associated with substantial morbidity and mortality. This review provides a comprehensive overview of the currently approved and emerging therapeutic options for the treatment of proteinuric CKD. As novel kidney protective agents have recently become available, the outcomes of patients with CKD could hopefully improve over the few decades ahead.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100060"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiobesity medications in adult and pediatric obesity and metabolic dysfunction-associated steatotic liver disease.","authors":"Natalie Rodriguez, Phillipp Hartmann","doi":"10.1016/j.pharmr.2025.100058","DOIUrl":"10.1016/j.pharmr.2025.100058","url":null,"abstract":"<p><p>Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are estimated to affect 13% and one-third of adults worldwide, respectively. The novel antiobesity medications achieve marked bodyweight loss and improve associated metabolic conditions, including MASLD. This review summarizes the development and mode of action and available published data on the effectiveness of approved and potential (off-label) antiobesity products in the management of adult and pediatric obesity and MASLD. Additionally, their safety is highlighted. The most effective antiobesity drugs evaluated in double-blind, randomized controlled trials include semaglutide, tirzepatide, and retatrutide with up to 10.8%, 17.8%, and 22.1% placebo-subtracted bodyweight loss, respectively, in adults after 48-72 weeks. Semaglutide also reduces placebo-subtracted body mass index mean by up to 16.7% in adolescents with obesity after 68 weeks. Moreover, these novel drugs are highly effective in treating adults with MASLD. Semaglutide and tirzepatide resolve metabolic dysfunction-associated steatohepatitis (MASH) without worsening of fibrosis placebo-subtracted in 41% and 53% of patients, respectively, after 52-72 weeks. Semaglutide, tirzepatide, and retatrutide reduce hepatic fat on magnetic resonance imaging-proton density fat fraction placebo-subtracted by 41%, 47%, and 81%, respectively, after 48-72 weeks. Tirzepatide also decreases fibrosis without worsening of MASH placebo-subtracted in up to 25% of patients. However, no pediatric trials have been conducted to study these novel drugs in biopsy-proven MASLD. In conclusion, the novel antiobesity drugs are highly effective in obesity and MASLD. However, more biopsy-based clinical trials are required to determine the effectiveness of these medications in adult metabolic dysfunction-associated steatohepatitis-associated fibrosis and pediatric MASLD. SIGNIFICANCE STATEMENT: This work reviews the current antiobesity medications, their structure, mode of action, and effectiveness. These medications are revolutionizing the management of metabolic dysfunction-associated steatotic liver disease by significantly reducing hepatic steatosis, disease activity, and even liver fibrosis.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100058"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144485478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antipsychotics and dietary interventions: Pharmacodynamics, pharmacokinetics, and synergisms in therapy.","authors":"Cristiana Perrotta, Carla Carnovale, Marco Pozzi, Clara De Palma, Davide Cervia, Maria Nobile, Emilio Clementi","doi":"10.1016/j.pharmr.2025.100061","DOIUrl":"10.1016/j.pharmr.2025.100061","url":null,"abstract":"<p><p>Antipsychotic (AP) medications are the primary treatment for severe mental illnesses, including schizophrenia and severe mood disorders. APs are currently categorized into typical or first-generation APs and atypical or second-generation APs. Although both first-generation and second-generation APs are considered effective in treating psychotic symptoms in severe mental disorders, they differ in their mechanisms, treatment strategies, and side effect profiles. Because of their potential motor and metabolic side effects, which often compromise patient adherence and clinical outcomes, whether and how to use APs remains controversial. The use of dietary interventions in combination with APs is emerging as a viable strategy to reduce AP adverse effects while maintaining their efficacy and enhance patient adherence to treatment. In contrast to drugs that possess a well defined molecular mechanism of action, dietary interventions act in pleiotropic ways by nature. While providing a holistic approach to patient care this pleiotropy needs to be analyzed and systematized to enhance the efficacy and safety of the combination of them with APs. Guidelines for this type of treatment are still needed. In this review, we explore the pharmacological properties, therapeutic applications, and limitations of APs, and discuss the potential benefits and limitations of those dietary interventions that are employed to improve the efficacy and counteract side effects of APs discussing also their mechanisms of action. Finally, we critically discuss the main results of clinical studies combining APs and dietary interventions and provide a view on future directions in terms of research and clinical use of these combinations. SIGNIFICANCE STATEMENT: Antipsychotic drugs are useful in a variety of psychiatric conditions, yet their use is hampered by issues of efficacy and safety. An important step toward therapy optimization is their use in combination with dietary interventions (ie, dietary supplements and nutraceuticals) that have shown promising results in clinical trials.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 4","pages":"100061"},"PeriodicalIF":17.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144143288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryoelectron microscopy as a tool for illuminating activation mechanisms of human class A orphan G protein-coupled receptors.","authors":"Isabella C Russell, Dongju Lee, Denise Wootten, Patrick M Sexton, Fabian Bumbak","doi":"10.1016/j.pharmr.2025.100056","DOIUrl":"10.1016/j.pharmr.2025.100056","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) are critically important medicinal targets, and the cryogenic electron microscopy (cryo-EM) revolution is providing novel high-resolution GPCR structures at a rapid pace. Orphan G protein-coupled receptors (oGPCRs) are a group of approximately 100 nonolfactory GPCRs for which endogenous ligands are unknown or not validated. The absence of modulating ligands adds difficulties to understanding the physiologic significance of oGPCRs and in the determination of high-resolution structures of isolated receptors that could facilitate drug discovery. Despite the challenges, cryo-EM structures of oGPCR-G protein complexes are emerging. This is being facilitated by numerous developments to stabilize GPCR-G protein complexes such as the use of dominant-negative G proteins, mini-G proteins, complex-stabilizing nanobodies or antibody fragments, and protein tethering methods. Moreover, many oGPCRs are constitutively active, which can facilitate complex formation in the absence of a known activating ligand. Consequently, in addition to providing templates for drug discovery, active oGPCR structures shed light on constitutive GPCR activation mechanisms. These comprise self-activation, whereby mobile extracellular portions of the receptor act as tethered agonists by occupying a canonical orthosteric-binding site in the transmembrane core, constitutive activity due to alterations to conserved molecular switches that stabilize inactive states of GPCRs, as well as receptors activated by cryptic ligands that are copurified with the receptor. Cryo-EM structures of oGPCRs are now being determined at a rapid pace and are expected to be invaluable tools for oGPCR drug discovery. SIGNIFICANCE STATEMENT: Orphan G protein-coupled receptors (GPCRs) provide large untapped potential for development of new medicines. Many of these receptors display constitutive activity, enabling structure determination and insights into observed GPCR constitutive activity including (1) self-activation by mobile receptor extracellular portions that function as tethered agonists, (2) modification of conserved motifs canonically involved in receptor quiescence and/or activation, and (3) activation by cryptic lipid ligands. Collectively, these studies advance fundamental understanding of GPCR function and provide opportunities for novel drug discovery.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100056"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player.","authors":"Yasmin Amy Divecha, Sanketh Rampes, Sabine Tromp, Sevda T Boyanova, Alice Fleckney, Mehmet Fidanboylu, Sarah Ann Thomas","doi":"10.1016/j.pharmr.2025.100052","DOIUrl":"10.1016/j.pharmr.2025.100052","url":null,"abstract":"<p><p>High fidelity neuronal signaling is enabled by a stable local microenvironment. A high degree of homeostatic regulation of the brain microenvironment, and its separation from the variable and potentially neurotoxic contents of the blood, is brought about by the central nervous system barriers. Evidence from clinical and preclinical studies implicates brain microcirculation, cerebral hypoperfusion, blood-brain barrier dysfunction, and reduced amyloid clearance in Alzheimer pathophysiology. Studying this dysregulation is key to understanding Alzheimer disease (AD), identifying drug targets, developing treatment strategies, and improving prescribing to this vulnerable population. This review has 2 parts: part 1 describes the cerebral microcirculation, cerebral blood flow, extracellular fluid drainage, and the neurovascular unit components with an emphasis on the blood-brain barrier, and part 2 summarizes how each aspect is altered in AD. Discussing the neurovascular unit structures separately allows us to conclude that aberrant pericytes are an early contributor and central to understanding AD pathophysiology. Pericytes have multiple functions including maintenance of blood-brain barrier integrity and the control of capillary blood flow, capillary stalling, neurovascular coupling, intramural periarterial drainage, glia-lymphatic (glymphatic) drainage, and consequently amyloid and tau clearance. Pericytes are vasoactive, express cholinergic and adrenergic receptors, and exhibit apolipoprotein E isoform-specific transport pathways. Hypoperfusion in AD is linked to a pericyte-mediated response. Deficient endothelial cell-pericyte (PDGBB-PDGFRβ) signaling loops cause pericyte dysfunction, which contributes and even initiates AD degeneration. We conclude that pericytes are central to understanding AD pathophysiology, are an interesting therapeutic target in AD, and have an emerging role in regenerative therapy. SIGNIFICANCE STATEMENT: Dysregulation and dysfunction of the neurovascular unit and fluid circulation (including blood, cerebrospinal fluid, and interstitial fluid) occurs in Alzheimer disease. A central player is the aberrant pericyte. This has fundamental implications to understanding disease pathophysiology and the development of therapies.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100052"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163501/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety in treatment: Classical pharmacotherapeutics and new avenues for addressing maternal depression and anxiety during pregnancy.","authors":"Merel Dagher, Catherine M Cahill, Anne M Andrews","doi":"10.1016/j.pharmr.2025.100046","DOIUrl":"10.1016/j.pharmr.2025.100046","url":null,"abstract":"<p><p>We aimed to review clinical research on the safety profiles of antidepressant drugs and associations with maternal depression and neonatal outcomes. We focused on neuroendocrine changes during pregnancy and their effects on antidepressant pharmacokinetics. Pregnancy-induced alterations in drug disposition and metabolism impacting mothers and their fetuses are discussed. We considered evidence for the risks of antidepressant use during pregnancy. Teratogenicity associated with ongoing treatment, new prescriptions during pregnancy, or pausing medication while pregnant was examined. The Food and Drug Administration advises caution regarding prenatal exposure to most drugs, including antidepressants, largely owing to a dearth of safety studies caused by the common exclusion of pregnant individuals in clinical trials. We contrasted findings on antidepressant use with the lack of treatment where detrimental effects to mothers and children are well researched. Overall, drug classes such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors appear to have limited adverse effects on fetal health and child development. In the face of an increasing prevalence of major mood and anxiety disorders, we assert that individuals should be counseled before and during pregnancy about the risks and benefits of antidepressant treatment given that withholding treatment has possible negative outcomes. Moreover, newer therapeutics, such as ketamine and κ-opioid receptor antagonists, warrant further investigation for use during pregnancy. SIGNIFICANCE STATEMENT: The safety of antidepressant use during pregnancy remains controversial owing to an incomplete understanding of how drug exposure affects fetal development, brain maturation, and behavior in offspring. This leaves pregnant people especially vulnerable, as pregnancy can be a highly stressful experience for many individuals, with stress being the biggest known risk factor for developing a mood or anxiety disorder. This review focuses on perinatal pharmacotherapy for treating mood and anxiety disorders, highlighting the current knowledge and gaps in our understanding of consequences of treatment.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100046"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclic nucleotide phosphodiesterases as drug targets.","authors":"Michy P Kelly, Viacheslav O Nikolaev, Leila Gobejishvili, Claire Lugnier, Christian Hesslinger, Peter Nickolaus, David A Kass, Walma Pereira de Vasconcelos, Rodolphe Fischmeister, Stefan Brocke, Paul M Epstein, Gary A Piazza, Adam B Keeton, Gang Zhou, Mohammad Abdel-Halim, Ashraf H Abadi, George S Baillie, Mark A Giembycz, Graeme Bolger, Gretchen Snyder, Kjetil Tasken, Nathaniel E B Saidu, Martina Schmidt, Manuela Zaccolo, Ralph T Schermuly, Hengming Ke, Rick H Cote, Soroush Mohammadi Jouabadi, Anton J M Roks","doi":"10.1016/j.pharmr.2025.100042","DOIUrl":"10.1016/j.pharmr.2025.100042","url":null,"abstract":"<p><p>Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"77 3","pages":"100042"},"PeriodicalIF":19.3,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}