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Current Protocols in Pharmacology最新文献

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Measurement of Receptor Signaling Bias 受体信号偏倚的测量
Current Protocols in Pharmacology Pub Date : 2016-09-16 DOI: 10.1002/cpph.11
Terry Kenakin
{"title":"Measurement of Receptor Signaling Bias","authors":"Terry Kenakin","doi":"10.1002/cpph.11","DOIUrl":"10.1002/cpph.11","url":null,"abstract":"<p>G protein–coupled receptors (GPCRs) are often pleiotropically linked to numerous cellular signaling mechanisms in cells, and it is now known that many agonists differentially activate some signaling pathways at the expense of others. The mechanism for this effect is the stabilization of different active receptor states by different agonists, and it leads to varying qualities of efficacy for different agonists. Agonist bias is a powerful mechanism to amplify beneficial signals and diminish harmful signals, and thus improve the overall profile of agonist ligands. This unit describes a method to quantify agonist bias with a scale that enables medicinal chemists to amplify or reduce these effects in new molecules. The method is based on the Black/Leff operational model and yields a statistical estimate of the confidence for bias measurements. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.11","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50903990","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}
引用次数: 6
Overview of Critical Parameters for the Design and Execution of a High-Throughput Screen for Allosteric Ligands 设计和执行高通量变构配体筛选的关键参数概述
Current Protocols in Pharmacology Pub Date : 2016-09-16 DOI: 10.1002/cpph.12
Andrew Alt
{"title":"Overview of Critical Parameters for the Design and Execution of a High-Throughput Screen for Allosteric Ligands","authors":"Andrew Alt","doi":"10.1002/cpph.12","DOIUrl":"10.1002/cpph.12","url":null,"abstract":"<p>Allosteric ligands modulate the activity of receptor targets by binding to sites that are distinct from the orthosteric (native agonist) binding site. Allosteric modulators have potential therapeutic advantages over orthosteric agonists and antagonists, including improved selectivity, and maintenance of the spatial and temporal fidelity of native signaling patterns. The identification of allosteric ligands presents unique challenges because of the requirement for screening in the presence of an orthosteric agonist, the small signal window that is produced by many allosteric modulators, the proclivity of allosteric modulators to exhibit activity switching within a chemotype (e.g., one compound may be a positive allosteric modulator while a close analog is a negative allosteric modulator), and probe dependence (differential interactions with different orthosteric agonists). Described in this unit are emerging strategies for the identification of allosteric ligands by high-throughput screening (HTS), including the use of multiple-add/multiple-read HTS assays and tool molecule-based screening formats. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50903825","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}
引用次数: 6
In Vitro Drug Metabolism Using Liver Microsomes 肝微粒体体外药物代谢研究
Current Protocols in Pharmacology Pub Date : 2016-09-16 DOI: 10.1002/cpph.9
Kathleen M. Knights, David M. Stresser, John O. Miners, Charles L. Crespi
{"title":"In Vitro Drug Metabolism Using Liver Microsomes","authors":"Kathleen M. Knights,&nbsp;David M. Stresser,&nbsp;John O. Miners,&nbsp;Charles L. Crespi","doi":"10.1002/cpph.9","DOIUrl":"10.1002/cpph.9","url":null,"abstract":"<p>Knowledge of the metabolic stability of newly discovered drug candidates eliminated by metabolism is essential for predicting the pharmacokinetic (PK) parameters that underpin dosing and dosage frequency. Further, characterization of the enzyme(s) responsible for metabolism (reaction phenotyping) allows prediction, at least at the qualitative level, of factors (including metabolic drug-drug interactions) likely to alter the clearance of both new chemical entities (NCEs) and established drugs. Microsomes are typically used as the enzyme source for the measurement of metabolic stability and for reaction phenotyping because they express the major drug-metabolizing enzymes cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), along with others that contribute to drug metabolism. Described in this unit are methods for microsome isolation, as well as for the determination of metabolic stability and metabolite formation (including kinetics). © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"74 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50904709","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}
引用次数: 81
Assays for Determination of Protein Concentration 蛋白质浓度测定方法
Current Protocols in Pharmacology Pub Date : 2016-06-01 DOI: 10.1002/cpph.3
Bradley J.S.C. Olson
{"title":"Assays for Determination of Protein Concentration","authors":"Bradley J.S.C. Olson","doi":"10.1002/cpph.3","DOIUrl":"10.1002/cpph.3","url":null,"abstract":"<p>Biochemical analysis of proteins relies on accurate quantification of protein concentration. Detailed in this appendix are some commonly used methods for protein analysis, e.g., Lowry, Bradford, bicinchoninic acid (BCA), UV spectroscopic, and 3-(4-carboxybenzoyl)quinoline-2-carboxaldehyde (CBQCA) assays. The primary focus of this report is assay selection, emphasizing sample and buffer compatibility. The fundamentals of generating protein assay standard curves and of data processing are considered, as are high-throughput adaptations of the more commonly used protein assays. Also included is a rapid, inexpensive, and reliable BCA assay of total protein in SDS-PAGE sample buffer that is used for equal loading of SDS-PAGE gels. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34535854","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}
引用次数: 48
Genetically Engineered Mouse Models of Pancreatic Cancer: The KPC Model (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), Its Variants, and Their Application in Immuno-oncology Drug Discovery 胰腺癌基因工程小鼠模型:KPC模型(LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre)、其变体及其在免疫肿瘤药物开发中的应用
Current Protocols in Pharmacology Pub Date : 2016-06-01 DOI: 10.1002/cpph.2
Jae W. Lee, Chad A. Komar, Fee Bengsch, Kathleen Graham, Gregory L. Beatty
{"title":"Genetically Engineered Mouse Models of Pancreatic Cancer: The KPC Model (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), Its Variants, and Their Application in Immuno-oncology Drug Discovery","authors":"Jae W. Lee,&nbsp;Chad A. Komar,&nbsp;Fee Bengsch,&nbsp;Kathleen Graham,&nbsp;Gregory L. Beatty","doi":"10.1002/cpph.2","DOIUrl":"10.1002/cpph.2","url":null,"abstract":"<p>Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths in the United States. For patients with unresectable disease, treatment options are limited and lack curative potential. Preclinical mouse models of PDAC that recapitulate the biology of human pancreatic cancer offer an opportunity for the rational development of novel treatment approaches that may improve patient outcomes. With the recent success of immunotherapy for subsets of patients with solid malignancies, interest is mounting in the possible use of immunotherapy for the treatment of PDAC. Considered in this unit is the value of genetic mouse models for characterizing the immunobiology of PDAC and for investigating novel immunotherapeutics. Several variants of these models are described, all of which may be used in drug development and for providing information on unique aspects of disease biology and therapeutic responsiveness. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34537369","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}
引用次数: 126
Mammalian Cell Tissue Culture Techniques 哺乳动物细胞组织培养技术
Current Protocols in Pharmacology Pub Date : 2016-06-01 DOI: 10.1002/cpph.1
Katy Phelan, Kristin M. May
{"title":"Mammalian Cell Tissue Culture Techniques","authors":"Katy Phelan,&nbsp;Kristin M. May","doi":"10.1002/cpph.1","DOIUrl":"10.1002/cpph.1","url":null,"abstract":"<p>Cultured tissues and cells are used extensively in physiological and pharmacological studies. In vitro cultures provide a means of examining cells and tissues without the complex interactions that would be present if the whole organism were studied. A number of special skills are required in order to preserve the structure, function, behavior, and biology of cells in culture. This unit describes the basic skills required to maintain and preserve cell cultures: maintaining aseptic technique, preparing media with the appropriate characteristics, passaging, freezing and storage, recovering frozen stocks, and counting viable cells. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"73 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/cpph.1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34535853","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}
引用次数: 6
Methods of Inducing Inflammatory Bowel Disease in Mice 诱导小鼠炎症性肠病的方法
Current Protocols in Pharmacology Pub Date : 2016-03-18 DOI: 10.1002/0471141755.ph0558s72
Byoungwook Bang, Lenard M. Lichtenberger
{"title":"Methods of Inducing Inflammatory Bowel Disease in Mice","authors":"Byoungwook Bang,&nbsp;Lenard M. Lichtenberger","doi":"10.1002/0471141755.ph0558s72","DOIUrl":"10.1002/0471141755.ph0558s72","url":null,"abstract":"<p>Animal models of experimentally induced inflammatory bowel disease (IBD) are useful for understanding more about the mechanistic basis of the disease, identifying new targets for therapeutic intervention, and testing novel therapeutics. This unit provides detailed protocols for five widely used mouse models of experimentally induced intestinal inflammation: chemical induction of colitis by dextran sodium sulfate (DSS), hapten-induced colitis via 2,4,6-trinitrobenzene sulfonic acid (TNBS), <i>Helicobacter</i>-induced colitis in <i>mdr1a</i>\u0000 <sup>−/−</sup> mice, the CD4<sup>+</sup> CD45RB<sup>hi</sup> SCID transfer colitis model, and the IL-10<sup>−/−</sup> colitis model. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0471141755.ph0558s72","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50807487","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}
引用次数: 18
Overview of Transgenic Glioblastoma and Oligoastrocytoma CNS Models and Their Utility in Drug Discovery 转基因胶质母细胞瘤和少星形细胞瘤中枢神经系统模型及其在药物开发中的应用综述
Current Protocols in Pharmacology Pub Date : 2016-03-18 DOI: 10.1002/0471141755.ph1437s72
Fuyi Chen, Albert Becker, Joseph LoTurco
{"title":"Overview of Transgenic Glioblastoma and Oligoastrocytoma CNS Models and Their Utility in Drug Discovery","authors":"Fuyi Chen,&nbsp;Albert Becker,&nbsp;Joseph LoTurco","doi":"10.1002/0471141755.ph1437s72","DOIUrl":"10.1002/0471141755.ph1437s72","url":null,"abstract":"<p>Many animal models have been developed to investigate the sources of central nervous system (CNS) tumor heterogeneity. Reviewed in this unit is a recently developed CNS tumor model using the <i>piggyBac</i> transposon system delivered by in utero electroporation, in which sources of tumor heterogeneity can be conveniently studied. Their applications for studying CNS tumors and drug discovery are also reviewed. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0471141755.ph1437s72","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50809480","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}
引用次数: 5
Overview of Genetically Engineered Mouse Models of Distinct Breast Cancer Subtypes 不同乳腺癌亚型的基因工程小鼠模型综述
Current Protocols in Pharmacology Pub Date : 2016-03-18 DOI: 10.1002/0471141755.ph1438s72
Jerry Usary, David Brian Darr, Adam D. Pfefferle, Charles M. Perou
{"title":"Overview of Genetically Engineered Mouse Models of Distinct Breast Cancer Subtypes","authors":"Jerry Usary,&nbsp;David Brian Darr,&nbsp;Adam D. Pfefferle,&nbsp;Charles M. Perou","doi":"10.1002/0471141755.ph1438s72","DOIUrl":"10.1002/0471141755.ph1438s72","url":null,"abstract":"<p>Advances in the screening of new therapeutic options have significantly reduced the breast cancer death rate over the last decade. Despite these advances, breast cancer remains the second leading cause of cancer death among women. This is due in part to the complexity of the disease, which is characterized by multiple subtypes that are driven by different genetic mechanisms and that likely arise from different cell types of origin. Because these differences often drive treatment options and outcomes, it is important to select relevant preclinical model systems to study new therapeutic interventions and tumor biology. Described in this unit are the characteristics and applications of validated genetically engineered mouse models (GEMMs) of basal-like, luminal, and claudin-low human subtypes of breast cancer. These different subtypes have different clinical outcomes and require different treatment strategies. These GEMMs can be considered faithful surrogates of their human disease counterparts. They represent alternative preclinical tumor models to cell line and patient-derived xenografts for preclinical drug discovery and tumor biology studies. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0471141755.ph1438s72","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50809830","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}
引用次数: 26
Drug Combinations: Tests and Analysis with Isoboles 药物组合:用异效孔进行试验和分析
Current Protocols in Pharmacology Pub Date : 2016-03-18 DOI: 10.1002/0471141755.ph0919s72
Ronald J. Tallarida
{"title":"Drug Combinations: Tests and Analysis with Isoboles","authors":"Ronald J. Tallarida","doi":"10.1002/0471141755.ph0919s72","DOIUrl":"10.1002/0471141755.ph0919s72","url":null,"abstract":"<p>Described in this unit are experimental and computational methods to detect and classify drug interactions. In most cases, this relates to two drugs or compounds with overtly similar effects, e.g., two analgesics or two anti-hypertensives. From the dose-response data of the individual drugs, it is possible to generate a curve, the isobole, which defines all dose combinations that are expected to yield a specified effect. The theory underlying the isobole involves the calculation of doses of drug A that are effectively equivalent to doses of drug B with that equivalence determining whether the isobole is linear or nonlinear. In either case, the isobole allows for a comparison with actual combination effects making it possible to determine whether the interaction is synergistic, additive, or sub-additive. Actual as well as illustrative data are employed to demonstrate experimental design and data analysis. © 2016 by John Wiley &amp; Sons, Inc.</p>","PeriodicalId":10871,"journal":{"name":"Current Protocols in Pharmacology","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/0471141755.ph0919s72","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50808401","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}
引用次数: 80
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