Download or read book Allosteric Receptor Modulation in Drug Targeting written by Norman G. Bowery and published by CRC Press. This book was released on 2016-04-19 with total page 378 pages. Available in PDF, EPUB and Kindle. Book excerpt: Offering a wide array of illustrations and tables in every chapter, this book extensively covers the principles of allosterism in reference to drug action and progresses to a detailed examination of individual ionotropic and G-protein coupled receptor systems-helping those new to the subject understand the importance of allosterism and providing th

Download or read book From Structure to Clinical Development Allosteric Modulation of G Protein Coupled Receptors written by and published by Academic Press. This book was released on 2020-05-13 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt: From Structure to Clinical Development: Allosteric Modulation of G Protein-Coupled Receptors, Volume 88, the latest release in the Advances in Pharmacology series, presents a variety of chapters from the best authors in the field. Chapters in this updated edition include Targeting muscarinic M1 receptor in neurodegeneration, Photo-switchable allosteric ligands, Computational approaches for the design of mGlu receptor allosteric modulators, Allosteric modulation of GLP-1 receptor in metabolic disorders, Group II mGluR roles in the nervous system and their roles in addiction, RAMPs as allosteric modulators of Class B GPCRs, Structure-based discovery and development of mGlu5 NAMs, and much more. Includes the authority and expertise of leading contributors in pharmacology Presents the latest release in the Advances in Pharmacology series

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

Download or read book Allosterism in Drug Discovery written by Dario Doller and published by Royal Society of Chemistry. This book was released on 2016-11-24 with total page 458 pages. Available in PDF, EPUB and Kindle. Book excerpt: Although the concept of allosterism has been known for over half a century, its application in drug discovery has exploded in recent years. The emergence of novel technologies that enable molecular-level ligand-receptor interactions to be studied in studied in unprecedented detail has driven this trend. This book, written by the leaders in this young research area, describes the latest developments in allosterism for drug discovery. Bringing together research in a diverse range of scientific disciplines, Allosterism in Drug Discovery is a key reference for academics and industrialists interested in understanding allosteric interactions. The book provides an in-depth review of research using small molecules as chemical probes and drug candidates that interact allosterically with proteins of relevance to life sciences and human disease. Knowledge of these interactions can then be applied in the discovery of the novel therapeutics of the future. This book will be useful for people working in all disciplines associated with drug discovery in academia or industry, as well as postgraduate students who may be working in the design of allosteric modulators.

Download or read book Extrasynaptic GABAA Receptors written by Adam C. Errington and published by Springer. This book was released on 2014-09-22 with total page 301 pages. Available in PDF, EPUB and Kindle. Book excerpt: GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAA and GABAB receptors. Recently, a novel form of GABAA receptor-mediated inhibition, termed “tonic” inhibition, has been described. Whereas synaptic GABAA receptors underlie classical “phasic” GABAA receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABAA receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABAA receptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This book highlights ongoing work examining the properties of recombinant and native extrasynaptic GABAA receptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABAA receptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.

Download or read book Allosteric Modulation for Drug Discovery written by Huailing Zhong and published by Wiley. This book was released on 2016-10-24 with total page 608 pages. Available in PDF, EPUB and Kindle. Book excerpt: A bridge for industrial and academic collaborations, this book overviews the concepts and therapeutic application of allosteric modulation to control protein function – explaining why it has gained strong momentum in drug discovery, technologies and methodologies to discover allosteric modulators, and allosteric modulator compounds. • Collects into one single resource the details on allosteric modulation of key drug targets, making for an encyclopedic coverage from basics to drug discovery applications • Describes methods to detect and analyze allosterism • Lets readers compare how allosteric modulators function and used across different platforms • Includes the major drug target classes with demonstrated allosteric modulation • Features a companion website with color images and protocols that readers can access

Download or read book Oligomerization and Allosteric Modulation in G Protein Coupled Receptors written by and published by Academic Press. This book was released on 2012-12-02 with total page 495 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this thematic volume of Progress in Molecular Biology and Translational Science, researchers reflect on recent developments and research surrounding G protein-coupled receptors. The chapters cover a large breadth of research, including GPCR role in stem cell function and pharmacology. Authors explore in-depth research techniques and applications of GPCR usage, covering theory, laboratory approaches, and unique qualities that make GPCRs a crucial tool in microbiological and cancer research. Contributions from leading authorities Informs and updates on all the latest developments in the field

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.

Download or read book Structural Biology in Drug Discovery written by Jean-Paul Renaud and published by John Wiley & Sons. This book was released on 2020-01-09 with total page 1367 pages. Available in PDF, EPUB and Kindle. Book excerpt: With the most comprehensive and up-to-date overview of structure-based drug discovery covering both experimental and computational approaches, Structural Biology in Drug Discovery: Methods, Techniques, and Practices describes principles, methods, applications, and emerging paradigms of structural biology as a tool for more efficient drug development. Coverage includes successful examples, academic and industry insights, novel concepts, and advances in a rapidly evolving field. The combined chapters, by authors writing from the frontlines of structural biology and drug discovery, give readers a valuable reference and resource that: Presents the benefits, limitations, and potentiality of major techniques in the field such as X-ray crystallography, NMR, neutron crystallography, cryo-EM, mass spectrometry and other biophysical techniques, and computational structural biology Includes detailed chapters on druggability, allostery, complementary use of thermodynamic and kinetic information, and powerful approaches such as structural chemogenomics and fragment-based drug design Emphasizes the need for the in-depth biophysical characterization of protein targets as well as of therapeutic proteins, and for a thorough quality assessment of experimental structures Illustrates advances in the field of established therapeutic targets like kinases, serine proteinases, GPCRs, and epigenetic proteins, and of more challenging ones like protein-protein interactions and intrinsically disordered proteins

Download or read book Receptor Receptor Interactions written by Kjell Fuxe and published by Springer Science & Business Media. This book was released on 2013-03-13 with total page 577 pages. Available in PDF, EPUB and Kindle. Book excerpt:

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.

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:

Download or read book Receptors P1 and P2 as Targets for Drug Therapy in Humans written by Robson Faria and published by BoD – Books on Demand. This book was released on 2020-03-11 with total page 112 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book aims to provide a brief update on the functions of purinergic receptors in various systems, in addition to the signaling pathway activated to mediate these functions. We address the influence of hypoxia by modulating the activity of these receptors under physiological and pathophysiological conditions. Additionally, we describe the mechanisms of induction of pain and inflammation in different systems. Finally, the book discusses some of the main bioinformatics tools currently used to improve or discover new prototypes capable of selectively acting on these receptors with estimated parameters of satisfactory solubility and toxicity for possible commercial implementation.

Download or read book Biased Signaling in Physiology Pharmacology and Therapeutics written by Brian J Arey and published by Elsevier. This book was released on 2014-06-05 with total page 317 pages. Available in PDF, EPUB and Kindle. Book excerpt: Biased Signaling in Physiology, Pharmacology and Therapeutics is a unique and essential reference for the scientific community concerning how conformational-dependent activation is a common phenomenon across many classes of receptors or signaling molecules. It discusses the role of conformational dynamics in leading to signaling bias across different classes of receptors and signaling molecules. By providing a broader view of signaling bias, this resource helps to explain common mechanisms shared across receptor classes and how this can be utilized to elucidate their cellular activity and better understand their therapeutic potential. Written for both new and established scientists in pharmacology, cell biology, biochemistry, and signal transduction, as well as physicians, this book clearly illustrates how biased receptor signaling can be utilized to develop and understand complex pharmacology. Chapters are each focused on a specific class of receptor or other important topic and make use of real-world examples illustrating how the latest research in signal transduction has led to a better understanding of pharmacology and cell biology. This structure creates a basis for understanding that physiological signalling bias has been selected by nature in order to provide complex and tissue- specific biological responses in the face of limited receptors and signaling pathways. This book provides a framework to reveal that these physiological mechanisms are not restricted to one receptor type or family and thus presents receptor signaling from a newer, more global perspective. Offers a unique and valuable resource on biased receptor signaling that provides a global view for better understanding pharmacology across many receptor families Integrates biased receptor signaling, physiology, and pharmacology to place this emerging science within the context of treating disease Includes important chapters on both the pharmaceutical and therapeutic implications of biased signaling

Download or read book Allosteric Modulation of the Human Cannabinoid 1 Receptor written by Derek M. Shore and published by . This book was released on 2014 with total page 202 pages. Available in PDF, EPUB and Kindle. Book excerpt: "The human cannabinoid-1 (CB1) receptor is a Class A, rhodopsin-like G protein-coupled receptor (GPCR). CB1 is found primarily in the central nervous system (CNS) where it participates in the regulation of neuronal activity; consequently, it is not surprising that this receptor has been implicated in numerous pathologies, including Alzheimer's disease, cancer, obesity, and pain. Unfortunately, many attempts at therapeutically targeting CB1 have failed, due to unacceptable CNS-related side effects; specifically, attempts to target CB1's orthosteric binding site (i.e. the primary binding site of endogenous, non-allosteric ligands) have been unsuccessful. These failures may be due to problems involving receptor subtype selectivity, a lack of functional selectivity, as well as a pathological interference with basal signaling. The ultimate goal of this research is to expand our understanding of CB1 signal transduction, at a molecular level, and to employ this knowledge in the development of CB1-based drug therapies. In pursuing this goal, we have used computational methods together with mutagenesis, synthesis, and pharmacological studies. The results of this work are presented here in four chapters, with each chapter acting as a foundation for subsequent investigation. In Chapter 1, we present results involving the importance of CB1's extracellular (EC) loops to its G protein-mediated signaling. Specifically, these results suggest that an ionic interaction between Lys-373 (of the EC-3 loop) and D2.63176 is important for G protein-mediated signaling. Our computational results suggest this salt bridge is important because it promotes an active conformation of the EC-3 loop, such that the EC-3 loop is pulled across the top of the receptor, `tethering' the EC-3 loop and transmembrane helix (TMH) 2. In addition, we report results that suggest that the EC-2 loop moves down (into the transmembrane core) upon activation. In Chapter 2, we report the binding site and mechanism of action of the negative CB1 allosteric modulator ORG27569. This compound has the paradoxical effects of increasing the equilibrium binding of CP55,940 (an orthosteric agonist), while at the same time antagonizing its G protein-mediated signaling. When applied alone, ORG27569 acts as an inverse agonist of G protein-mediated signaling, as well as an agonist of the ERK signaling pathway. Our results suggest that ORG27569 binds in the TMH3/6/7 region of CB1 (extending extracellularly), and promotes an intermediate conformation of CB1. In addition, ORG27569 may antagonize the G protein-mediated signaling of CP55,940 by sterically blocking conformational changes of the EC-2 and EC-3 loops, as well as by packing tightly against TMH6. We also reported that ORG27569's inverse agonism is dependent upon the formation of a hydrogen bond between its piperidine nitrogen and K3.28192. In Chapter 3, we use our model of ORG27569 docked at CB1 (in the presence of CP55,940) to design, synthesize, and characterize four analogs of ORG27569. These compounds were designed using three different strategies: 1) to form a new hydrogen bond between the analog(s) and D6.58366; 2) to form a new aromatic stack between the analog(s) an F3.25189; and 3) to test steric packing between the analog(s) and TMH6/7. The experimental results revealed that these four compounds have a unique and rich pharmacological profile. The analog PHR018 is a more efficacious negative allosteric modulator than ORG27569 (whereas PHR017 is a less efficacious modulator). The analog PHR016 is a `classical' allosteric modulator (i.e. an allosteric modulator that only affects the binding/signaling of an orthosteric ligand, with no functional effects when applied alone); PHR016's sole functional effect is to antagonize the G protein-mediated signaling of CP55,940. Finally, the analog PHR019 was observed to be a completely biased agonist for CB1 ERK signaling. To our knowledge, PHR019 is the only completely biased agonist for the ERK signaling pathway that targets a GPCR. In addition, none of these analogs acted as inverse agonists of G protein-mediated signaling. Altogether, these results suggest the remarkable therapeutic potential of CB1 allosteric-based therapies, due to the analogs' unprecedented level of functional control, as well the analogs' noninterference with basal G protein-mediated signaling. In Chapter 4, we report the binding site and mechanism of action of lipoxin A4, a positive allosteric modulator of CB1. Specifically, we used the Forced-Biased Metropolis Monte Carlo simulated annealing method (MMC), Glide docking studies, as well as molecular dynamics to identify lipoxin A4's binding site at CB1. These results suggest that lipoxin A4 binds in the TMH3/6/7 region of CB1, extending extracellularly. Unlike ORG27569 (which sterically blocks conformational changes of the EC loops), lipoxin A4 forms several electrostatic interactions with the EC loops. By forming these interactions, lipoxin A4 promotes an active conformation of the EC-3 (and EC-2) loops, thereby stabilizing an active conformation of CB1. Together, these results describe important conformational changes in the extracellular region of CB1, the binding site and mechanism of action of ORG27569, the development of unique ORG27569 analogs (including a biased agonist of the ERK pathway), and finally the binding site and mechanism of action of the positive allosteric modulator, lipoxin A4. Hopefully, this work (and future studies) will aid in the development of new therapies that target CB1."--Abstract from author supplied metadata.

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.

Download or read book GABA And Glutamate written by Janko Samardzic and published by BoD – Books on Demand. This book was released on 2018-03-21 with total page 139 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book collates the contributions of a selected number of neuroscientists that are interested in the molecular, preclinical, and clinical aspects of neurotransmission research. The seven chapters in this book address the latest research/review data related to GABA/glutamate system's organization and function, the structure of receptors, subtypes and their ligands, as well as the translational approach and clinical implications. The book offers readers a rich collection of data regarding current and future applications of GABA and glutamate neurotransmission, including promising research strategies and potential clinical benefits.