Pharmacological Reviews最新文献

{"title":"International Union of Basic and Clinical Pharmacology. CXVII: Taste 2 receptors: Structures, functions, activators and blockers.","authors":"Maik Behrens","doi":"10.1124/pharmrev.123.001140","DOIUrl":"10.1124/pharmrev.123.001140","url":null,"abstract":"<p><p>Bitter perception plays a critical role for the detection of potentially harmful substances in food items for most vertebrates. The detection of bitter compounds is facilitated by specialized receptors located in taste buds of the oral cavity. This work focuses on the receptors, including their sensitivities, structure-function relationships, agonists and antagonists. Moreover, the existence of numerous bitter taste receptor variants in the human population and the fact that several of them affect individual bitter tasting profoundly, is discussed as well. The identification of bitter taste receptors in numerous tissues outside the oral cavity and their multiple proposed roles in these tissues is also described briefly. Although this work is mainly focused on human bitter taste receptors, it is imperative to compare human bitter taste with that of other animals to understand which evolutionary forces might have shaped bitter taste receptors and their functions and to distinguish apparent typical human from rather general features. For the readers who are not too familiar with the gustatory system short descriptions of taste anatomy, signal transduction and oral bitter taste receptor expression are included in the beginning of this article. <b>Significance Statement</b> Apart from their role as sensors for potentially harmful substances in the oral cavity, the numerous additional roles of bitter taste receptors in tissues outside the gustatory system have received much attention recently. For the careful assessment of functions inside and outside the taste system a solid knowledge about the specific and general pharmacological features of these receptors and the growing toolbox available for studying them is imperative and provided in this work.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":""},"PeriodicalIF":19.3,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142110626","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":"Topically Applied Therapies for the Treatment of Skin Disease: Past, Present, and Future.","authors":"Marc Brown, Adrian Williams, Robert P Chilcott, Brendan Brady, Jon Lenn, Charles Evans, Lynn Allen, William J McAuley, Mubinah Beebeejaun, Jasmin Haslinger, Claire Beuttel, Raquel Vieira, Florencia Guidali, Margarida Miranda","doi":"10.1124/pharmrev.123.000549","DOIUrl":"10.1124/pharmrev.123.000549","url":null,"abstract":"<p><p>The purpose of this review is to summarize essential biological, pharmaceutical, and clinical aspects in the field of topically applied medicines that may help scientists when trying to develop new topical medicines. After a brief history of topical drug delivery, a review of the structure and function of the skin and routes of drug absorption and their limitations is provided. The most prevalent diseases and current topical treatment approaches are then detailed, the organization of which reflects the key disease categories of autoimmune and inflammatory diseases, microbial infections, skin cancers, and genetic skin diseases. The complexity of topical product development through to large-scale manufacturing along with recommended risk mitigation approaches are then highlighted. As such topical treatments are applied externally, patient preferences along with the challenges they invoke are then described, and finally the future of this field of drug delivery is discussed, with an emphasis on areas that are more likely to yield significant improvements over the topical medicines in current use or would expand the range of medicines and diseases treatable by this route of administration. SIGNIFICANCE STATEMENT: This review of the key aspects of the skin and its associated diseases and current treatments along with the intricacies of topical formulation development should be helpful in making judicious decisions about the development of new or improved topical medicines. These aspects include the choices of the active ingredients, formulations, the target patient population's preferences, limitations, and the future with regard to new skin diseases and topical medicine approaches.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"689-790"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446690","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. CXVI: NC-IUPHAR and <i>Pharmacological Reviews</i>: 30+ Years of Collaboration-Editorial.","authors":"Eliot H Ohlstein","doi":"10.1124/pharmrev.124.001409","DOIUrl":"https://doi.org/10.1124/pharmrev.124.001409","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"76 5","pages":"622-624"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988564","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":"Pharmacology of Hydrogen Sulfide and Its Donors in Cardiometabolic Diseases.","authors":"Hai-Jian Sun, Qing-Bo Lu, Xue-Xue Zhu, Zhang-Rong Ni, Jia-Bao Su, Xiao Fu, Guo Chen, Guan-Li Zheng, Xiao-Wei Nie, Jin-Song Bian","doi":"10.1124/pharmrev.123.000928","DOIUrl":"10.1124/pharmrev.123.000928","url":null,"abstract":"<p><p>Cardiometabolic diseases (CMDs) are major contributors to global mortality, emphasizing the critical need for novel therapeutic interventions. Hydrogen sulfide (H₂S) has garnered enormous attention as a significant gasotransmitter with various physiological, pathophysiological, and pharmacological impacts within mammalian cardiometabolic systems. In addition to its roles in attenuating oxidative stress and inflammatory response, burgeoning research emphasizes the significance of H₂S in regulating proteins via persulfidation, a well known modification intricately associated with the pathogenesis of CMDs. This review seeks to investigate recent updates on the physiological actions of endogenous H₂S and the pharmacological roles of various H₂S donors in addressing diverse aspects of CMDs across cellular, animal, and clinical studies. Of note, advanced methodologies, including multiomics, intestinal microflora analysis, organoid, and single-cell sequencing techniques, are gaining traction due to their ability to offer comprehensive insights into biomedical research. These emerging approaches hold promise in characterizing the pharmacological roles of H₂S in health and diseases. We will critically assess the current literature to clarify the roles of H₂S in diseases while also delineating the opportunities and challenges they present in H₂S-based pharmacotherapy for CMDs. SIGNIFICANCE STATEMENT: This comprehensive review covers recent developments in H₂S biology and pharmacology in cardiometabolic diseases CMDs. Endogenous H₂S and its donors show great promise for the management of CMDs by regulating numerous proteins and signaling pathways. The emergence of new technologies will considerably advance the pharmacological research and clinical translation of H₂S.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"846-895"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311274","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":"Conotoxins Targeting Voltage-Gated Sodium Ion Channels.","authors":"Shengrong Pei, Nan Wang, Zaoli Mei, Dongting Zhangsun, David J Craik, J Michael McIntosh, Xiaopeng Zhu, Sulan Luo","doi":"10.1124/pharmrev.123.000923","DOIUrl":"10.1124/pharmrev.123.000923","url":null,"abstract":"<p><p>Voltage-gated sodium (Na_V) channels are intimately involved in the generation and transmission of action potentials, and dysfunction of these channels may contribute to nervous system diseases, such as epilepsy, neuropathic pain, psychosis, autism, and cardiac arrhythmia. Many venom peptides selectively act on Na_V channels. These include conotoxins, which are neurotoxins secreted by cone snails for prey capture or self-defense but which are also valuable pharmacological tools for the identification and/or treatment of human diseases. Typically, conotoxins contain two or three disulfide bonds, and these internal crossbraces contribute to conotoxins having compact, well defined structures and high stability. Of the conotoxins containing three disulfide bonds, some selectively target mammalian Na_V channels and can block, stimulate, or modulate these channels. Such conotoxins have great potential to serve as pharmacological tools for studying the functions and characteristics of Na_V channels or as drug leads for neurologic diseases related to Na_V channels. Accordingly, discovering or designing conotoxins targeting Na_V channels with high potency and selectivity is important. The amino acid sequences, disulfide bond connectivity, and three-dimensional structures are key factors that affect the biological activity of conotoxins, and targeted synthetic modifications of conotoxins can greatly improve their activity and selectivity. This review examines Na_V channel-targeted conotoxins, focusing on their structures, activities, and designed modifications, with a view toward expanding their applications. SIGNIFICANCE STATEMENT: Na_V channels are crucial in various neurologic diseases. Some conotoxins selectively target Na_V channels, causing either blockade or activation, thus enabling their use as pharmacological tools for studying the channels' characteristics and functions. Conotoxins also have promising potential to be developed as drug leads. The disulfide bonds in these peptides are important for stabilizing their structures, thus leading to enhanced specificity and potency. Together, conotoxins targeting Na_V channels have both immediate research value and promising future application prospects.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"828-845"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141446689","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":"Intestinal Barrier, Immunity and Microbiome: Partners in the Depression Crime.","authors":"Eva M Medina-Rodríguez, José Martínez-Raga, Yolanda Sanz","doi":"10.1124/pharmrev.124.001202","DOIUrl":"10.1124/pharmrev.124.001202","url":null,"abstract":"<p><p>Depression is a highly prevalent disorder and a leading cause of disability worldwide. It has a major impact on the affected individual and on society as a whole. Regrettably, current available treatments for this condition are insufficient in many patients. In recent years, the gut microbiome has emerged as a promising alternative target for treating and preventing depressive disorders. However, the microbes that form this ecosystem do not act alone but are part of a complicated network connecting the gut and the brain that influences our mood. Host cells that are in intimate contact with gut microbes, such as the epithelial cells forming the gut barrier and the immune cells in their vicinity, play a key role in the process. These cells continuously shape immune responses to maintain healthy communication between gut microbes and the host. In this article, we review how the interplay among epithelial cells, the immune system, and gut microbes mediates gut-brain communication to influence mood. We also discuss how advances in our knowledge of the mechanisms underlying the gut-brain axis could contribute to addressing depression. SIGNIFICANCE STATEMENT: This review does not aim to systematically describe intestinal microbes that might be beneficial or detrimental for depression. We have adopted a novel point of view by focusing on potential mechanisms underlying the crosstalk between gut microbes and their intestinal environment to control mood. These pathways could be targeted by well defined and individually tailored dietary interventions, microbes, or microbial metabolites to ameliorate depression and decrease its important social and economic impact.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"956-969"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141860523","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 Development of Cannabinoids as Therapeutic Agents in the United States.","authors":"Conor H Murray, Brenda M Gannon, Peter J Winsauer, Ziva D Cooper, Marcus S Delatte","doi":"10.1124/pharmrev.123.001121","DOIUrl":"10.1124/pharmrev.123.001121","url":null,"abstract":"<p><p>Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents while underscoring the risks related to interfering with the endogenous system during nonmedical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility to ultimately extend our knowledge of the risks and benefits of cannabinoids for patients and providers. SIGNIFICANCE STATEMENT: This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"915-955"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288379","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":"International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology.","authors":"Jyrki P Kukkonen, Laura H Jacobson, Daniel Hoyer, Maiju K Rinne, Stephanie L Borgland","doi":"10.1124/pharmrev.123.000953","DOIUrl":"10.1124/pharmrev.123.000953","url":null,"abstract":"<p><p>The orexin system consists of the peptide transmitters orexin-A and -B and the G protein-coupled orexin receptors OX₁ and OX₂ Orexin receptors are capable of coupling to all four families of heterotrimeric G proteins, and there are also other complex features of the orexin receptor signaling. The system was discovered 25 years ago and was immediately identified as a central regulator of sleep and wakefulness; this is exemplified by the symptomatology of the disorder narcolepsy with cataplexy, in which orexinergic neurons degenerate. Subsequent translation of these findings into drug discovery and development has resulted to date in three clinically used orexin receptor antagonists to treat insomnia. In addition to sleep and wakefulness, the orexin system appears to be a central player at least in addiction and reward, and has a role in depression, anxiety and pain gating. Additional antagonists and agonists are in development to treat, for instance, insomnia, narcolepsy with or without cataplexy and other disorders with excessive daytime sleepiness, depression with insomnia, anxiety, schizophrenia, as well as eating and substance use disorders. The orexin system has thus proved an important regulator of numerous neural functions and a valuable drug target. Orexin prepro-peptide and orexin receptors are also expressed outside the central nervous system, but their potential physiological roles there remain unknown. SIGNIFICANCE STATEMENT: The orexin system was discovered 25 years ago and immediately emerged as an essential sleep-wakefulness regulator. This discovery has tremendously increased the understanding of these processes and has thus far resulted in the market approval of three orexin receptor antagonists, which promote more physiological aspects of sleep than previous hypnotics. Further, orexin receptor agonists and antagonists with different pharmacodynamic properties are in development since research has revealed additional potential therapeutic indications. Orexin receptor signaling is complex and may represent novel features.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"625-688"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432520","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 Enduring Impact of <i>Pharmacological Reviews</i>-Editorial.","authors":"David R Sibley","doi":"10.1124/pharmrev.124.000991","DOIUrl":"10.1124/pharmrev.124.000991","url":null,"abstract":"","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"76 5","pages":"620-621"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11331920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988565","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":"The Art of Finding the Right Drug Target: Emerging Methods and Strategies.","authors":"Zi-Chang Jia, Xue Yang, Yi-Kun Wu, Min Li, Debatosh Das, Mo-Xian Chen, Jian Wu","doi":"10.1124/pharmrev.123.001028","DOIUrl":"10.1124/pharmrev.123.001028","url":null,"abstract":"<p><p>Drug targets are specific molecules in biological tissues and body fluids that interact with drugs. Drug target discovery is a key component of drug discovery and is essential for the development of new drugs in areas such as cancer therapy and precision medicine. Traditional in vitro or in vivo target discovery methods are time-consuming and labor-intensive, limiting the pace of drug discovery. With the development of modern discovery methods, the discovery and application of various emerging technologies have greatly improved the efficiency of drug discovery, shortened the cycle time, and reduced the cost. This review provides a comprehensive overview of various emerging drug target discovery strategies, including computer-assisted approaches, drug affinity response target stability, multiomics analysis, gene editing, and nonsense-mediated mRNA degradation, and discusses the effectiveness and limitations of the various approaches, as well as their application in real cases. Through the review of the aforementioned contents, a general overview of the development of novel drug targets and disease treatment strategies will be provided, and a theoretical basis will be provided for those who are engaged in pharmaceutical science research. SIGNIFICANCE STATEMENT: Target-based drug discovery has been the main approach to drug discovery in the pharmaceutical industry for the past three decades. Traditional drug target discovery methods based on in vivo or in vitro validation are time-consuming and costly, greatly limiting the development of new drugs. Therefore, the development and selection of new methods in the drug target discovery process is crucial.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":" ","pages":"896-914"},"PeriodicalIF":19.3,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311272","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}