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Conformationally Constrained Analogs Of Org27569 As Allosteric Modulators Of Cb1 Cannabinoid Receptor
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Book Synopsis Conformationally Constrained Analogs of Org27569 as Allosteric Modulators of CB1 Cannabinoid Receptor by : Siddhi Honavar
Download or read book Conformationally Constrained Analogs of Org27569 as Allosteric Modulators of CB1 Cannabinoid Receptor written by Siddhi Honavar and published by . This book was released on 2015 with total page 45 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Cannabinoid receptors have become the focus of research due to their importance as targets for treating a number of disorders. These receptors which are a part of the G-protein coupled receptor (GPCR) superfamily are of two subtypes, CB1 receptors which are present abundantly in the brain and in small traces in the peripheral and adipose tissues and CB2 receptors which are predominantly found in the immune cells. The cannabinoid receptors were always known to show its function through the orthosteric ligand binding, but the discovery of allosteric site on the CB1 receptors, has opened up a whole new horizon for research. Three of Organon analogs displayed a noticeable allosterism at the CB1 receptors, wherein they were negative allosteric modulators of function but positive allosteric modulators of binding of orthosteric ligand at the CB1 receptor. The SAR around these three molecules has not been explored as much, and as all three almost shared the same phamacophoric properties, Org 27569 was selected as the lead compound. Org 27569 which is a negative allosteric modulator of CB1 receptor has been found to also show hypophagic effect independent of the presence of the CB1 receptor, and hence pointing towards the possibility of it's off target binding which is a major limitation in its further development as a drug. Exploring the SAR around Org 27569 would give a better insight into the molecules requirements for allosteric modulation at CB1 receptor. The Conformational restriction approach is adopted as a tool for molecular modification and design of the analogs. This projects aims at synthesizing conformationally constrained analogs of Org 27569 as GAT700 and GAT701, to explore the receptor binding and functional selectivity of the allosteric modulators at the CB1 cannabinoid receptor.
Book Synopsis Design and Synthesis of Allosteric Modulators of CB1 Cannabinoid Receptor by : Abhijit R. Kulkarni
Download or read book Design and Synthesis of Allosteric Modulators of CB1 Cannabinoid Receptor written by Abhijit R. Kulkarni and published by . This book was released on 2011 with total page 47 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cannabinoid receptors are a major class of cell-membrane receptors which belong to the super-family of G protein-coupled receptors (GPCRs) and are targeted for the treatment of several diseases including neurodegenerative diseases, cancer, obesity, inflammation and neuropathic and inflammatory pain. Two subtypes of cannabinoid receptors, namely, CB1 and CB2, have been cloned and studied more intensively. CB1 receptor is the most abundant GPCR in the brain, and a wide range of selective and potent CB1-receptor ligands for its orthosteric site have been developed. However, their therapeutic utility has been limited due to side effects associated with indiscriminate cannabinoid receptor activation and propensity for receptor desensitization. This problem is exemplified by the recent cancellation of the Phase III clinical trials of the CB1 antagonists / inverse agonists Taranabant and Otenabant and the manufacturer's (Sanofi-Aventis) voluntary withdrawal of the marketed drug Rimonabant in the European Union. Rimonabant (Acomplia), which was approved as an adjunctive weight-loss drug in Europe, suffered serious-dose related gastrointestinal and psychiatric side effects such as depression and suicidal ideation. Other approaches such as development of CB1 neutral as well as peripherally-acting antagonists have shown therapeutic promise and reduced side effects in recently published preclinical studies.A promising alternative approach is the development of CB1 allosteric modulators which by binding to a sub-type specific and topographically distinct site from the orthosteric site can either enhance or inhibit the action of endocannabinoids and thus act more selectively to tune the CB signaling in a site- and event-specific manner. Recently high-throughput screening (HTS) from two different laboratories has identified two different classes of ligand (e.g., Org27569 and PSNCBAM-1) exhibiting negative allosteric modulation at CB1 receptors. Due to the unavailability of the cannabinoid receptor's crystal structure, characterization of the binding site(s) of these allosteric modulators is lacking. Availability of such data will prove instrumental in elucidating their molecular basis for activity and in developing highly selective, potent CB1 allosteric modulators. The objective of the present study is to develop covalent probes (both photo-activatable and electrophilic) based upon the parent structure of Org27569 bearing azido and isothiocyanate functionality at the judiciously chosen positions. Using Ligand-Assisted Protein Structure approach (LAPS), which involves use of such probes for labeling the receptor covalently followed by MS analysis of the protein and validating the resulting data with site-directed mutagenesis and molecular modeling studies, the chemical nature and tertiary structure of the active allosteric sites of CB1 can be elucidated. Additionally, we propose to synthesize an iodinated analog of Org27569 to facilitate development of radiometric competitive binding assays directed at CB1 allosteric site. We also propose to synthesize two hybrid analogs of Org27569 and PSNCBAM-1 to help understand structural requirements for CB1 allosteric site and facilitate development of future structure-activity relationship studies.
Book Synopsis The Study of Allosteric Modulator Sites at the Cannabinoid CB1 Receptor by : Teresa S. Barber
Download or read book The Study of Allosteric Modulator Sites at the Cannabinoid CB1 Receptor written by Teresa S. Barber and published by . This book was released on 2009 with total page 47 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Org 27569, Org 27759 and Org 29647 are the first discovered allosteric modulators of the cannabinoid CB1 receptor. These ligands are thought to bind to "accessory binding sites" at the receptor . Binding of the Org allosteric modulators has been shown to affect the affinities of various CB1 ligands, but to reduce the efficacy of these ligands. The goal of this research project was to understand at a molecular level, the origins of the effects produced by the Org allosteric modulators. The study was begun by performing AM1 conformational searches for each allosteric modulator using the Spartan molecular modeling suite . Those conformers within 2.00 kcal/mol of the global minimum energy conformer of each modulator were subjected to geometry optimization in Jaguar (Schrodinger, Inc). Org27569 was then targeted for further study. Org 27569 has been reported to increase the CB1 affinity of the non-classical cannabinoid, (1R3R4R)-3-[2-hydroxy-4-(1,1-dimethylheptylphenyl]-4-(3-hydroxy-propyl)cyclohexab-1-ol, CP-55,940, but to reduce its efficacy. Since the binding site of Org27569 is unknown, the MMC program was then employed to identify potential binding sites. The MMC program is a cavity biased method that uses Monte Carlo simulated annealing of chemical potential to identify small-molecule binding sites in protein structures via a molecular fragment approach [F. Guarnieri and M. Mezei, JACS 118, 8493, 1996]. The receptor was placed in a virtual cell. At high chemical potentials, the box is filled with completely with the fragment of interest. As the chemical potential decreases, fragments with less favorable interactions are stripped away. Indole and piperidine rings were used as fragments because they constitute the two major structural features of Org 27569. Three common binding sites for both the indole and piperidine fragments were identified. These areas were R3.50 (intracellular domain), W4.50 (possible homodimer interface) and in the transmembrane region between helices 1 and 2 (interacting with CP55,940). These were considered possible interaction sites for the following reasons: (1) If interactions occurred between the allosteric modulator and R3.50, this would block the interaction site of the G-protein and thus impair signalling. (2) W4.50 is commonly found in GPCR dimer interfaces. If the CB1 receptor functions as a dimer, Org27569 would impair activation by blocking dimer formation. (3) The TMH1-2 site site would allow the affinity of CP55940 to increase because it would block CP55940 exit from CB1. At the same time, the TMH1-2 site dock would constrain TMH6 from moving during activation by tethering the EC-3 loop. This should also result in impaired signal transduction. Future studies will involve mutation studies of each allosteric binding site identified in this project to determine the allosteric binding site for Org 27569"--Abstract from author supplied metadata.
Book Synopsis Behavioral Neurobiology of the Endocannabinoid System by : Dave Kendall
Download or read book Behavioral Neurobiology of the Endocannabinoid System written by Dave Kendall and published by Springer Science & Business Media. This book was released on 2009-08-14 with total page 418 pages. Available in PDF, EPUB and Kindle. Book excerpt: The endocannabinoid signaling system is a key modulator of central nervous function. This volume, essential reading for interested neuroscientists, provides in-depth coverage of the roles of the endocannabinoid signaling system in the neurobiology of behavior.
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 Neuronal Nicotinic Receptors by : Stephen P. Arneric
Download or read book Neuronal Nicotinic Receptors written by Stephen P. Arneric and published by Wiley-Liss. This book was released on 1999 with total page 450 pages. Available in PDF, EPUB and Kindle. Book excerpt: Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities Edited by Stephen P. Arneric and Jorge D. Brioni Nicotine's efficacy in the treatment of pain and anxiolysis, and its usefulness as a memory enhancer, have been suspected for many years, but research into the molecular biology of nicotinic acetylcholine receptors (nAChRs) traditionally has focused on smoking cessation. Now, thanks to recent technological advances in the molecular biology and electrophysiology of nAChRs, an abundance of evidence has emerged in support of nAChR ligands in the treatment of a range of CNS disorders, including Alzheimer's disease, Parkinson's disease, neuropathic pain, attention deficit disorder, and depression. Featuring contributions from an international team of experts in the field, this volume provides researchers and clinicians with a comprehensive review of nAChRs, their molecular biology, pharmacology, and clinical implications. Moving from the molecular to the clinical levels, the authors explore the latest developments in all areas of nAChR research, including: Molecular biology and biochemistry of nAChRs The physiological roles of nAChRs Pharmacokinetics of nicotine-like alkaloids Recent breakthroughs and emerging trends in nAChR medicinal chemistry Current and emerging therapeutic applications of novel nAChR ligands. A timely, authoritative review of basic research into nAChRs and their role in the development of new therapeutic strategies in the treatment of a range of various CNS diseases, Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities is required reading for neuroscientists, pharmacologists, medicinal chemists, biological psychiatrists, and psychopharmacologists.
Book Synopsis Allosterism in Drug Discovery by : Dario Doller
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.
Book Synopsis Free Energy Calculations by : Christophe Chipot
Download or read book Free Energy Calculations written by Christophe Chipot and published by Springer Science & Business Media. This book was released on 2007-01-08 with total page 528 pages. Available in PDF, EPUB and Kindle. Book excerpt: Free energy constitutes the most important thermodynamic quantity to understand how chemical species recognize each other, associate or react. Examples of problems in which knowledge of the underlying free energy behaviour is required, include conformational equilibria and molecular association, partitioning between immiscible liquids, receptor-drug interaction, protein-protein and protein-DNA association, and protein stability. This volume sets out to present a coherent and comprehensive account of the concepts that underlie different approaches devised for the determination of free energies. The reader will gain the necessary insight into the theoretical and computational foundations of the subject and will be presented with relevant applications from molecular-level modelling and simulations of chemical and biological systems. Both formally accurate and approximate methods are covered using both classical and quantum mechanical descriptions. A central theme of the book is that the wide variety of free energy calculation techniques available today can be understood as different implementations of a few basic principles. The book is aimed at a broad readership of graduate students and researchers having a background in chemistry, physics, engineering and physical biology.
Book Synopsis Resolution Pharmacology - Innovative Therapeutic Approaches Based on the Biology of Resolution to Control Chronic Diseases of Western Societies by : Mauro Perretti
Download or read book Resolution Pharmacology - Innovative Therapeutic Approaches Based on the Biology of Resolution to Control Chronic Diseases of Western Societies written by Mauro Perretti and published by Frontiers Media SA. This book was released on 2019-11-04 with total page 205 pages. Available in PDF, EPUB and Kindle. Book excerpt: In this eBook, we have grouped together 16 original contributions which have addressed the translational potential for therapeutics developed on the conceptual framework of the resolution of inflammation. The take home message of our effort, and the efforts of our colleagues who wrote these pieces, is that completely different drugs can be designed and modelled on the mediators and targets of resolution. By implementing this 180° shift in the way we plan the drug development programme (that is by focusing on agonists and/or promoting the actions of pro-resolution agonists) we can offer a fresh approach to the clinical management of chronic diseases that affect the modern society. With this series of articles we foresee the birth of Resolution Pharmacology. The 16 contributions presented herein confirm the broad relevance of pro-resolving physio-pharmacology with the description of pro-resolving mechanisms in distinct diseases, from atherosclerosis and heart infarct, to cystic fibrosis and diabetes. This testifies on one hand the fundamental role that inflammatory mechanisms play in virtually all pathological settings and, on the other hand, the great potential that a novel approach to anti-inflammatory therapy by exploiting resolution mediators and targets may have. Thus, while there is broad recognition that evidence-based interventions have transformed cardiovascular, inflammation and endocrine care, new therapies are still needed for growing numbers of patients with unmet needs. As an example, an estimated 17 million people world-wide die annually of cardiovascular diseases, particularly heart attacks and strokes. Cardiovascular diseases occur almost equally in men and women and are the leading cause of death and morbidity worldwide. It is estimated that only 1/1,000 compounds entering preclinical testing are then trialled in man and the actual cost of developing a new therapeutic into clinical practice has grown exponentially over the past two decades (estimated $1.2B). Over the last 20 years or more, scientists have appreciated the biology of the resolution of inflammation, which provides a new paradigm in our understanding of the inflammatory process with the appreciation of genetic, molecular and cellular mechanisms that are engaged to actively resolve inflammation. The ‘resolution of acute inflammation’ is enabled by counter-regulatory checkpoints to terminate the host reaction while at the same time promoting healing and repair. The potential of lipid mediators to enact pro-resolving effects in the context of cystic fibrosis is presented by Recchiuti et al., while Fredman reasons on the potential for these molecules in atherosclerosis. This resonates well with the contributions from Bäck and colleagues who have focused on pro-resolving receptors to offer vasculo-protection in intimal hyperplasia and more generally in cardiovascular disease. On the same vein is the scholar contribution of Leoni and Soehnlein who focus on heart disease, with Qin et al. presenting the latest findings on the effect of an Annexin A1-derived peptide in myocardial infarction. Hansen et al. and de Gaetano et al. bring in the complexity of diabetes and associated morbidity with a focus on specialised pro-resolving lipid mediators but also introducing the potential of dietary approaches. As the western diet favours disease, an omega-3 rich diet can lead to higher availability of lipid mediators to afford tissue protection if not reverting its pathological status. Docosahexaenoic acid and its bioactive derivatives are endowed with potent anti-nociceptive properties following bone fracture, as shown by Zhang et al. The broad relevance of the pharmacological approach reaches the skin with Resolvin D1 protecting against UV irradiation (Saito et al.). Reduced skin inflammation is also achieved with an Annexin A1 peptide that impacts on the outcome of heterologous transplantation (Lacerda et al.). Indeed, modulating the phenotype of immune cells can provide long lasting beneficial outcomes, as attained with CDK inhibitors (Cartwright et al.) and PI3K inhibitors in experimental gout (Galvao et al.). Such an effect is also achieved with a third group of pro-resolving therapeutics, the melanocortin receptor agonists, with important modulation of macrophage reactivity (Patruno et al.) with Spana et al., providing new pharmacology following selective activation of the MC1 receptor. Finally, Hopkin et al. discuss the potential for targeting immune cell trafficking as a way to control immune mediated diseases, bringing in not only pro-resolving mediator agonists, but also approaches to reduce chemo/cytokine gradients or modulating S1P and 11-beta hydroxysteroid dehydrogenase. Finally, we wish to highlight that this wealth of science has also bought to the forefront specific pro-resolving receptors (including FPR2/ALX, GPR32, ChemR23 and MC1), all G protein coupled receptors that are therefore amenable to pharmacological exploitation for drug discovery programmes. We see that not only agonists to the receptors can be developed, some of them modelled on the natural ligands (e.g. resolvins, lipoxins, Annexin A1-derived peptides or melanocortin peptides), but also that the creativity of this pharmacology can be attained through biased ligands and positive allosteric modulators. Deep knowledge of pro-resolving receptor biology and their cell-specific signalling can accelerate the generation of novel anti-inflammatory depicted on the resolution of inflammation. In conclusion, with this eBook, we propose time is ready to exploit the concepts of resolution and use its targets and mediators for the identification of better drugs to establish ‘Resolution Pharmacology’. We predict Resolution Pharmacology will represent an important innovation in the way common diseases will be treated in the next decades of this millennium.
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 The 29th Annual Symposium of the International Cannabinoid Research Society by :
Download or read book The 29th Annual Symposium of the International Cannabinoid Research Society written by and published by . This book was released on 2019-06-29 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: 29th Annual Symposium of the International Cannabinoid Research Society. Bethesda, Maryland. June 29 - July 4, 2019.
Book Synopsis Adenosine Receptors in the Nervous System by : J. A. Ribeiro
Download or read book Adenosine Receptors in the Nervous System written by J. A. Ribeiro and published by Taylor & Francis Group. This book was released on 1989 with total page 252 pages. Available in PDF, EPUB and Kindle. Book excerpt: A satellite Symposium on Adenosine Receptors in the Nervous System was held in April 1989 in Portugal. This book contains the manuscripts of the papers presented by the participants, who were from Europe, America and Asia.
Download or read book GPCRs written by Beata Jastrzebska and published by Academic Press. This book was released on 2019-09-12 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: GPCRS: Structure, Function, and Drug Discovery provides a comprehensive overview of recent discoveries and our current understanding of GPCR structure, signaling, physiology, pharmacology and methods of study. In addition to the fundamental aspects of GPCR function and dynamics, international experts discuss crystal structures, GPCR complexes with partner proteins, GPCR allosteric modulation, biased signaling through protein partners, deorphanization of GPCRs, and novel GPCR-targeting ligands that could lead to the development of new therapeutics against human diseases. GPCR association with, and possible therapeutic pathways for, retinal degenerative diseases, Alzheimer's disease, Parkinson's disease, cancer and diabetic nephropathy, among other illnesses, are examined in-depth.
Book Synopsis Chirality in Drug Design and Synthesis by : C. Brown
Download or read book Chirality in Drug Design and Synthesis written by C. Brown and published by Academic Press. This book was released on 2013-10-22 with total page 264 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chirality in Drug Design and Synthesis is a collection of papers that discusses the property of asymmetry in the structural and synthetic chemistry of natural products, including the significance of chirality in medicinal chemistry. These papers examine the need for the preparation and study of pure enantiomers of chiral drug substances and their mechanism of interaction with enzymes and receptors. These papers also investigate the techniques in studying these interactions, as well as analyze the methods for their synthesis in enantiomerically pure form. One paper discusses the pharmacological and pharmacokinetic analyses made that point to the differences in the activity and disposition of enantiometric pairs. Another paper reviews the implications of the neglect of stereoselectivity at the different levels during the examination process of racemic drugs. Since no general guidelines exists for the development of drugs with chiral centers, one paper suggests a case-by-case approach in evaluating the safety and efficacy of drugs, particularly as regards how isomers differ in their effects. This collection is suitable for the pharmacologist, medicinal chemists, toxicologists, mechanistic chemists and synthetic organic chemists.
Book Synopsis Chemoinformatics Approaches to Structure- and Ligand-Based Drug Design by : Adriano D. Andricopulo
Download or read book Chemoinformatics Approaches to Structure- and Ligand-Based Drug Design written by Adriano D. Andricopulo and published by Frontiers Media SA. This book was released on 2019-02-05 with total page 415 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chemoinformatics is paramount to current drug discovery. Structure- and ligand-based drug design strategies have been used to uncover hidden patterns in large amounts of data, and to disclose the molecular aspects underlying ligand-receptor interactions. This Research Topic aims to share with a broad audience the most recent trends in the use of chemoinformatics in drug design. To that end, experts in all areas of drug discovery have made their knowledge available through a series of articles that report state-of-the-art approaches. Readers are provided with outstanding contributions focusing on a wide variety of topics which will be of great value to those interested in the many different and exciting facets of drug design.
Download or read book Lipid Domains written by and published by Academic Press. This book was released on 2015-06-08 with total page 393 pages. Available in PDF, EPUB and Kindle. Book excerpt: Current Topics in Membranes is targeted toward scientists and researchers in biochemistry and molecular and cellular biology, providing the necessary membrane research to assist them in discovering the current state of a particular field and in learning where that field is heading. This volume offers an up to date presentation of current knowledge in the field of Lipid Domains. Written by leading experts Contains original material, both textual and illustrative, that should become a very relevant reference material The material is presented in a very comprehensive manner Both researchers in the field and general readers should find relevant and up-to-date information
Book Synopsis Allosteric Modulation of Amino Acid Receptors by : Eric A. Barnard
Download or read book Allosteric Modulation of Amino Acid Receptors written by Eric A. Barnard and published by Raven Press (ID). This book was released on 1989 with total page 430 pages. Available in PDF, EPUB and Kindle. Book excerpt:
