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Discovery Optimization And Validation Efforts Towards Positive Allosteric Modulators Of The Glucagon Like Peptide 1 Receptor And Discovery Of A Novel Series Of Glucagon Like Peptide 1 Receptor Noncompetitive Antagonists
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Book Synopsis Discovery, Optimization, and Validation Efforts Towards Positive Allosteric Modulators of the Glucagon-like Peptide 1 Receptor and Discovery of a Novel Series of Glucagon-like Peptide 1 Receptor Noncompetitive Antagonists by : Kellie D'Nee Nance
Download or read book Discovery, Optimization, and Validation Efforts Towards Positive Allosteric Modulators of the Glucagon-like Peptide 1 Receptor and Discovery of a Novel Series of Glucagon-like Peptide 1 Receptor Noncompetitive Antagonists written by Kellie D'Nee Nance and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Exploring Aspects of Allosteric Modulation and Bias Signalling at the Glucagon-like Peptide-1 Receptor by : Emilia Elizabeth Savage
Download or read book Exploring Aspects of Allosteric Modulation and Bias Signalling at the Glucagon-like Peptide-1 Receptor written by Emilia Elizabeth Savage and published by . This book was released on 2015 with total page 544 pages. Available in PDF, EPUB and Kindle. Book excerpt: The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of insulin biosynthesis and secretion, and is one of the key therapeutic targets in the management of type II diabetes mellitus and obesity. Like most GPCRs, the GLP-1R is pleiotropically coupled, to physiologically relevant signalling pathways including cAMP formation, intracellular calcium (iCa2+) mobilization and phosphorylation of extracellular signal regulated kinases 1 and 2 (pERK1/2). The GLP-1R is a class B G protein-coupled receptor (GPCR) that has the ability to be activated by multiple endogenous ligands including four variants of GLP-1 (the predominant form being GLP-1(7-36)NH2) and oxyntomodulin. This receptor is also activated by the exogenous peptide exendin-4 and allosteric ligands such as the Novo Nordisk Compound 2 and Eli Lily 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP). These allosteric ligands also have unique properties compared to orthosteric exogenous ligands including the ability to alter the signalling of the GLP-1R in response to orthosteric ligands. These effects can be different depending on which orthosteric ligand is co bound to the receptor, a effect known as probe-dependence. This thesis identifies a novel case of probe dependence, the ability of allosteric ligands to modify the signalling mediated by metabolites of endogenous ligands that were previously considered to be 'inert' breakdown products that may open up new avenues for allosteric drug discovery.It is widely accepted that insulin secretion downstream of GLP-1R activation is critically dependent on cAMP formation, but recent evidence is also emerging for an essential role of regulatory proteins such as [beta]-arrestins and G protein-coupled receptor kinases (GRK). The canonical role of these regulatory proteins is to terminate GPCR signalling and promote receptor internalization. However, more recently, roles as scaffolding proteins that can regulate G protein-independent signalling have emerged. Consequently, the studies comprising this thesis illustrate distinct recruitment profiles of regulatory proteins to the GLP-1R in response to multiple endogenous and exogenous ligands. This thesis identifies differential actions of allosteric modulators on GLP-1R peptide ligands ('probe dependence'), thus demonstrating differential responses of receptor signalling with respect to both orthosteric and allosteric ligands, highlighting the ability for both ligand- and pathway-specific effects ('biased signalling'). Collectively, this work further demonstrates the potential benefits of biased signalling and allosteric modulation, but may also influence the approaches and precautions that must be considered in the design, identification and development of small molecules for therapeutic use.
Book Synopsis Exploring the Structure, Function and Regulation of the Human Glucagon-like Peptide-1 Receptor by : Yan Huang
Download or read book Exploring the Structure, Function and Regulation of the Human Glucagon-like Peptide-1 Receptor written by Yan Huang and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion and promotes?-cell function via its receptor (GLP-1R), which therefore is a validated target for the treatment of type 2 diabetes. Due to difficulties with peptide therapeutics, it is important to find small-molecule GLP-1R agonists. This leads to a need to understand the structure, function and regulation of the receptor, particularly, differences between agonisms mediated by GLP-1 (orthosteric agonist) and small molecules. The GLP-1R contains a putative N-terminal signal peptide sequence, which is assessed here by recombinantly expressing several epitope-tagged GLP-1R constructs in HEK293 cells. The findings demonstrate that the GLP-1R is expressed predominately at the plasma membrane and also slightly cytosolic. Only fully glycosylated, mature form of the receptor is able to traffic to the cell surface and performs the function. The signal peptide sequence of the GLP-1R is essential for synthesis. After fulfilling the function, this sequence is cleaved and thus not part of the mature protein. The cleavage of signal peptide is critical for processing and trafficking of the GLP-1R. Based on one of these constructs generated here, a cell line (HEK293: GLP-1R-EGFP) with stable expression of the visible GLP-1R is established, which allows observations and determinations for ligand-mediated receptor internalisation in real time. Compound 2 (6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline) has been described as a GLP-1R allosteric modulator and agonist. Findings here that compound 2-mediated agonisms on both the wild-type (WT) GLP-1R and the mutant with removal of the N-terminal domain provide direct evidence for the allosteric agonism. Interestingly, compound 2-mediated cAMP response is enhanced by orthosteric antagonist exendin 9-39, but the latter inhibits receptor internalisation mediated by compound 2. Recently, it has been hypothesised that the binding of GLP-1 allows a sequence of NRTFD (Asn63-Asp67) in the N-terminus of the GLP-1R to interact with another part of the receptor and cause agonism. This was examined here by generating receptor mutants and synthetic peptides. Findings here that Asp67 plays a key role in stabilising the N-terminal structure of the GLP-1R and thus is critical for processing and trafficking of the receptor protein do not support such hypothesis although synthetic NRTFD mediates a weak and partial agonism on the WTGLP-1R.
Book Synopsis The Metabotropic Glutamate Receptors by : P. Jeffrey Conn
Download or read book The Metabotropic Glutamate Receptors written by P. Jeffrey Conn and published by Springer Science & Business Media. This book was released on 2013-03-09 with total page 284 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Metabotropic Glutamate Receptors offers state-of-the-art summaries and reviews of virtually everything known today about metabotropic glutamate receptors (mGluRs), including their molecular biology, pharmacology, anatomical distribution, and physiological and pathological roles. Illuminating the overall role played by this crucial class of receptors in brain function, the book also pinpoints those areas in which there is the greatest continuing need for focused research. Because mGluRs have the potential for participating in virtually all known functions of the central nervous system (CNS), the opportunity now exists to develop pharmacological agents that can potentially alter many brain disease processes by selective interaction with precise CNS functions. With its critical and insightful reviews, The Metabotropic Glutamate Receptors will immediately become your essential key to the development of novel treatment strategies for the widest variety of neurological disorders.
Book Synopsis Concepts and Principles of Pharmacology by : James E. Barrett
Download or read book Concepts and Principles of Pharmacology written by James E. Barrett and published by Springer Nature. This book was released on 2019-12-24 with total page 466 pages. Available in PDF, EPUB and Kindle. Book excerpt: Celebrating 100 years of HEP, this volume will discuss key pharmacological discoveries and concepts of the past 100 years. These discoveries have dramatically changed the medical treatment paradigms of many diseases and these concepts have and will continue to shape discovery of new medicinies. Newly evolving technologies will similarly be discussed as they will shape the future of the pharmacology and, accordingly, medical therapy.
Book Synopsis Practical Psychopharmacology by : Joseph F. Goldberg
Download or read book Practical Psychopharmacology written by Joseph F. Goldberg and published by Cambridge University Press. This book was released on 2021-04-29 with total page 611 pages. Available in PDF, EPUB and Kindle. Book excerpt: A practical guide translating clinical trials findings, across major psychiatric disorders, to devise tailored, evidence-based treatments.
Book Synopsis Protein Allostery in Drug Discovery by : Jian Zhang
Download or read book Protein Allostery in Drug Discovery written by Jian Zhang and published by Springer Nature. This book was released on 2019-11-09 with total page 384 pages. Available in PDF, EPUB and Kindle. Book excerpt: The book focuses on protein allostery in drug discovery. Allosteric regulation, ʹthe second secret of lifeʹ, fine-tunes virtually most biological processes and controls physiological activities. Allostery can both cause human diseases and contribute to development of new therapeutics. Allosteric drugs exhibit unparalleled advantages compared to conventional orthosteric drugs, rendering the development of allosteric modulators as an appealing strategy to improve selectivity and pharmacodynamic properties in drug leads. The Series delineates the immense significance of protein allostery—as demonstrated by recent advances in the repertoires of the concept, its mechanistic mechanisms, and networks, characteristics of allosteric proteins, modulators, and sites, development of computational and experimental methods to predict allosteric sites, small-molecule allosteric modulators of protein kinases and G-protein coupled receptors, engineering allostery, and the underlying role of allostery in precise medicine. Comprehensive understanding of protein allostery is expected to guide the rational design of allosteric drugs for the treatment of human diseases. The book would be useful for scientists and students in the field of protein science and Pharmacology etc.
Book Synopsis Design of Hybrid Molecules for Drug Development by : Michael Decker
Download or read book Design of Hybrid Molecules for Drug Development written by Michael Decker and published by Elsevier. This book was released on 2017-04-05 with total page 354 pages. Available in PDF, EPUB and Kindle. Book excerpt: Design of Hybrid Molecules for Drug Development reviews the principles, advantages, and limitations involved with designing these groundbreaking compounds. Beginning with an introduction to hybrid molecule design and background as to their need, the book goes on to explore a range of important hybrids, with hybrids containing natural products, molecules containing NO- and H2S-donors, dual-acting compounds acting as receptor ligands and enzyme inhibitors, and the design of photoresponsive drugs all discussed. Drawing on practical case studies, the hybridization of molecules for development as treatments for a number of key diseases is then outlined, including the design of hybrids for Alzheimer's, cancer, and malaria. With its cutting-edge reviews of breaking developments in this exciting field, the book offers a novel approach for all those working in the design, development, and administration of drugs for a range of debilitating disorders. Highlights an approach unimpaired by the limitations of the classical search for lead structures - one of the core problems in modern drug development processes, making the content of high relevance for both academic and non-academic drug development processes Pulls together research and design techniques in a novel way to give researchers the best possible platform from which to review the approaches and techniques applied Compares the advantages and disadvantages of these compounds Includes the very latest developments, such as photoactivatable and photo-responsive drugs
Book Synopsis Drug Discovery and Evaluation: Pharmacological Assays by : Hans Vogel
Download or read book Drug Discovery and Evaluation: Pharmacological Assays written by Hans Vogel and published by Springer Science & Business Media. This book was released on 2007-10-30 with total page 2118 pages. Available in PDF, EPUB and Kindle. Book excerpt: The new edition of this successful reference offers both cutting-edge and classic pharmacological methods. Thoroughly revised and expanded to two volumes, it offers an updated selection of the most frequently used assays for reliably detecting the pharmacological effects of potential drugs. Every chapter has been updated, and numerous assays have been added. Each of the more than 1,000 assays comprises a detailed protocol outlining purpose and rationale, and a critical assessment of the results and their pharmacological and clinical relevance.
Book Synopsis Computational Methods for GPCR Drug Discovery by : Alexander Heifetz
Download or read book Computational Methods for GPCR Drug Discovery written by Alexander Heifetz and published by Humana Press. This book was released on 2017-11-30 with total page 436 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume looks at modern computational strategies and techniques used in GPCR drug discovery including structure and ligand-based approaches and cheminformatics. The chapters in this book describe how these approaches can be applied to address key drug discovery issues, such as receptor structure modelling, function and dynamics, prediction of protein-water-ligand interactions and binding kinetics, free energy of binding, interconversion between agonists and antagonists, deorphanization of GPCRs, and the discovery of biased and allosteric modulators. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary software and tools, step-by-step, readily reproducible modelling protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and unique,Computational Methods for GPCR Drug Discovery is a valuable resource for structural and molecular biologists, computational and medicinal chemists, pharmacologists, and drug designers.
Download or read book Gaba written by Chikako Tanaka and published by Springer Science & Business Media. This book was released on 1996 with total page 354 pages. Available in PDF, EPUB and Kindle. Book excerpt: Highlighting the current developments and future directions in GABA research, the ambitious aim of this topical volume is to cover GABA from the molecular mechanisms of its transmission to new targets for pharmaceutical research. Distinguished scientists at the forefront of GABA research were invited to contribute reviews on glutamate decarboxylase and autoimmunity, molecular structure and functional regulation of GABA transporters, transmitter release and GABA receptor regulation, GABA receptor subtypes and functional regulation, and GABA receptor ligands and their therapeutic application. Describing the latest advances in what has become a rapidly-evolving field, this volume will prove immensely valuable to neuroscientists, pharmacologists, biochemists, and physiologists working in the field of GABA research.
Book Synopsis Encyclopedia of Biology by : Don Rittner
Download or read book Encyclopedia of Biology written by Don Rittner and published by Infobase Publishing. This book was released on 2004-08 with total page 417 pages. Available in PDF, EPUB and Kindle. Book excerpt: Contains approximately 800 alphabetical entries, prose essays on important topics, line illustrations, and black-and-white photographs.
Book Synopsis Allosteric Modulation of G Protein-Coupled Receptors by : Robert Laprairie
Download or read book Allosteric Modulation of G Protein-Coupled Receptors written by Robert Laprairie and published by Academic Press. This book was released on 2022-02-05 with total page 214 pages. Available in PDF, EPUB and Kindle. Book excerpt: Allosteric Modulation of G Protein-Coupled Receptors reviews fundamental information on G protein-coupled receptors (GPCRs) and allosteric modulation, presenting original research in the area and collectively providing a comprehensive description of key issues in GPCR allosteric modulation. The book provides background on core concepts of molecular pharmacology while also introducing the most important advances and studies in the area. It also discusses key methodologies. This is an essential book for researchers and advanced students engaged in pharmacology, toxicology and pharmaceutical sciences training and research. Many of the GPCR-targeted drugs released in the past decade have specifically worked via allosteric mechanisms. Unlike direct orthosteric-acting compounds that occupy a similar receptor site to that of endogenous ligands, allosteric modulators alter GPCR-dependent signaling at a site apart from the endogenous ligand. Recent methodological and analytical advances have greatly improved our ability to understand the signaling mechanisms of GPCRs. We now know that allostery is a common regulatory mechanism for all GPCRs and not – as we once believed – unique to a few receptor subfamilies. Introduces background on core concepts of molecular pharmacology, including statistical analyses, non-linear regression, complex models and GPCR-dependent signal transduction as they relate to allosteric modulation Discusses critical advances and landmark studies, including discoveries in the area of GPCR allosteric modulation, which are reviewed for their importance in positive and negative regulation, protein-protein interactions, and small molecule drug discovery Includes key methodologies used to study allosteric modulation at the in silico, in vitro, and in vivo levels of drug discovery and characterization
Book Synopsis Essential Clinical Anesthesia by : Charles Vacanti
Download or read book Essential Clinical Anesthesia written by Charles Vacanti and published by Cambridge University Press. This book was released on 2011-07-11 with total page 1191 pages. Available in PDF, EPUB and Kindle. Book excerpt: The clinical practice of anesthesia has undergone many advances in the past few years, making this the perfect time for a new state-of-the-art anesthesia textbook for practitioners and trainees. The goal of this book is to provide a modern, clinically focused textbook giving rapid access to comprehensive, succinct knowledge from experts in the field. All clinical topics of relevance to anesthesiology are organized into 29 sections consisting of more than 180 chapters. The print version contains 166 chapters that cover all of the essential clinical topics, while an additional 17 chapters on subjects of interest to the more advanced practitioner can be freely accessed at www.cambridge.org/vacanti. Newer techniques such as ultrasound nerve blocks, robotic surgery and transesophageal echocardiography are included, and numerous illustrations and tables assist the reader in rapidly assimilating key information. This authoritative text is edited by distinguished Harvard Medical School faculty, with contributors from many of the leading academic anesthesiology departments in the United States and an introduction from Dr S. R. Mallampati. This book is your essential companion when preparing for board review and recertification exams and in your daily clinical practice.
Book Synopsis Molecular Diagnostics: Promises and Possibilities by : Mousumi Debnath
Download or read book Molecular Diagnostics: Promises and Possibilities written by Mousumi Debnath and published by Springer Science & Business Media. This book was released on 2010-01-29 with total page 527 pages. Available in PDF, EPUB and Kindle. Book excerpt: A rapid development in diverse areas of molecular biology and genetic engineering resulted in emergence of variety of tools. These tools are not only applicable to basic researches being carried out world over, but also exploited for precise detection of abnormal conditions in plants, animals and human body. Although a basic researcher is well versed with few techniques used by him/her in the laboratory, they may not be well acquainted with methodologies, which can be used to work out some of their own research problems. The picture is more blurred when the molecular diagnostic tools are to be used by physicians, scientists and technicians working in diagnostic laboratories in hospitals, industry and academic institutions. Since many of them are not trained in basics of these methods, they come across several gray areas in understanding of these tools. The accurate application of molecular diagnostic tools demands in depth understanding of the methodology for precise detection of the abnormal condition of living body. To meet the requirements of a good book on molecular diagnostics of students, physicians, scientists working in agricultural, veterinary, medical and pharmaceutical sciences, it needs to expose the reader lucidly to: Give basic science behind commonly used tools in diagnostics Expose the readers to detailed applications of these tools and Make them aware the availability of such diagnostic tools The book will attract additional audience of pathologists, medical microbiologists, pharmaceutical sciences, agricultural scientists and veterinary doctors if the following topics are incorporated at appropriate places in Unit II or separately as a part of Unit-III in the book. Molecular diagnosis of diseases in agricultural crops Molecular diagnosis of veterinary diseases. Molecular epidemiology, which helps to differentiate various epidemic strains and sources of disease outbreaks. Even in different units of the same hospital, the infections could be by different strains of the same species and the information becomes valuable for infection control strategies. Drug resistance is a growing problem for bacterial, fungal and parasitic microbes and the molecular biology tools can help to detect the drug resistance genes without the cultivation and in vitro sensitivity testing. Molecular diagnostics offers faster help in the selection of the proper antibiotic for the treatment of tuberculosis, which is a major problem of the in the developing world. The conventional culture and drug sensitivity testing of tuberculosis bacilli is laborious and time consuming, whereas molecular diagnosis offers rapid drug resistant gene detection even from direct clinical samples. The same approach for HIV, malaria and many more diseases needs to be considered. Molecular diagnostics in the detection of diseases during foetal life is an upcoming area in the foetal medicine in case of genetic abnormalities and infectious like TORCH complex etc. The book will be equally useful to students, scientists and professionals working in the field of molecular diagnostics.
Book Synopsis Color Atlas of Pharmacology by : Heinz Lüllmann
Download or read book Color Atlas of Pharmacology written by Heinz Lüllmann and published by . This book was released on 2000 with total page 404 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Acute Pain Management by : Raymond S. Sinatra
Download or read book Acute Pain Management written by Raymond S. Sinatra and published by Cambridge University Press. This book was released on 2009-04-27 with total page 729 pages. Available in PDF, EPUB and Kindle. Book excerpt: This textbook provides an overview of pain management useful to specialists as well as non-specialists, surgeons, and nursing staff.
