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Modulation Of Cannabinoid Receptor Activity By Allosteric Modulators Inverse Agonists And Receptor Binding Partners
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Book Synopsis Modulation of Cannabinoid Receptor Activity by Allosteric Modulators, Inverse Agonists and Receptor Binding Partners by : Mariam Mohammed Mahmoud
Download or read book Modulation of Cannabinoid Receptor Activity by Allosteric Modulators, Inverse Agonists and Receptor Binding Partners written by Mariam Mohammed Mahmoud and published by . This book was released on 2014 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Modulation of Cannabinoid Receptor Activity by Allosteric Modulators, Inverse Agonists and Receptor Binding Partners by : Mariam Mohammed Mahmoud
Download or read book Modulation of Cannabinoid Receptor Activity by Allosteric Modulators, Inverse Agonists and Receptor Binding Partners written by Mariam Mohammed Mahmoud and published by . This book was released on 2015 with total page 370 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Allosteric Modulation of the Human Cannabinoid-1 Receptor by : Derek M. Shore
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.
Book Synopsis Ligand-Induced Modulation of the Cannabinoid Receptor 1 by : Rachel Dopart
Download or read book Ligand-Induced Modulation of the Cannabinoid Receptor 1 written by Rachel Dopart and published by . This book was released on 2019 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
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 Phytocannabinoids by : A. Douglas Kinghorn
Download or read book Phytocannabinoids written by A. Douglas Kinghorn and published by Springer. This book was released on 2017-01-24 with total page 137 pages. Available in PDF, EPUB and Kindle. Book excerpt: The book presents the current state of the art on phytocannnabinoid chemistry and pharmacology and will be of much use to those wishing to understand the current landscape of the exciting and intriguing phytocannabinoid science. The focus is on natural product cannabinoids which have been demonstrated to act at specific receptor targets in the CNS.
Book Synopsis Handbook of Cannabis and Related Pathologies by : Victor R Preedy
Download or read book Handbook of Cannabis and Related Pathologies written by Victor R Preedy and published by Academic Press. This book was released on 2016-12-31 with total page 1382 pages. Available in PDF, EPUB and Kindle. Book excerpt: Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment is the first book to take an interdisciplinary approach to the understanding of cannabis use and misuse. Recent worldwide trends toward decriminalizing marijuana for medical use have increased legal use of the drug and recreational use remains high, making cannabis one of the most commonly used drugs. Cannabis has a wide range of adverse neurological effects, and use and abuse can lead to physical, social, and psychopathological issues that are multifarious and complex. Effective understanding and treatment requires knowledge of the drug’s effects from across scientific disciplines. This book provides an overview of the biological and pharmacological components of the cannabis plant, outlines its neurological, social, and psychopathological effects, assists in the diagnosis and screening for use and dependency, and aids researchers in developing effective treatments for cannabis-related issues and disorders. Fully illustrated, with contributions from internationally recognized experts, it is the go-to resource for neuroscientists, pharmacologists, pathologists, public-health workers, and any other researcher who needs an in-depth and cross-disciplinary understanding of cannabis and its effects. Comprehensive chapters include an abstract, key facts, mini dictionary of terms, and summary points Presents illustrations with at least six figures, tables, and diagrams per chapter Provides a one-stop-shopping synopsis of everything to do with cannabis and its related pathology, from chemicals and cells, individuals and communities, and diagnosis and treatment Offers an integrated and informed synopsis of the complex issues surrounding cannabis as a substance, its use, and its misuse
Book Synopsis An Introduction to Markov State Models and Their Application to Long Timescale Molecular Simulation by : Gregory R. Bowman
Download or read book An Introduction to Markov State Models and Their Application to Long Timescale Molecular Simulation written by Gregory R. Bowman and published by Springer Science & Business Media. This book was released on 2013-12-02 with total page 148 pages. Available in PDF, EPUB and Kindle. Book excerpt: The aim of this book volume is to explain the importance of Markov state models to molecular simulation, how they work, and how they can be applied to a range of problems. The Markov state model (MSM) approach aims to address two key challenges of molecular simulation: 1) How to reach long timescales using short simulations of detailed molecular models. 2) How to systematically gain insight from the resulting sea of data. MSMs do this by providing a compact representation of the vast conformational space available to biomolecules by decomposing it into states sets of rapidly interconverting conformations and the rates of transitioning between states. This kinetic definition allows one to easily vary the temporal and spatial resolution of an MSM from high-resolution models capable of quantitative agreement with (or prediction of) experiment to low-resolution models that facilitate understanding. Additionally, MSMs facilitate the calculation of quantities that are difficult to obtain from more direct MD analyses, such as the ensemble of transition pathways. This book introduces the mathematical foundations of Markov models, how they can be used to analyze simulations and drive efficient simulations, and some of the insights these models have yielded in a variety of applications of molecular simulation.
Book Synopsis Cannabinoids and Pain by : Samer N. Narouze
Download or read book Cannabinoids and Pain written by Samer N. Narouze and published by Springer Nature. This book was released on 2021-07-01 with total page 339 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents a well-balanced view of the potential medical use of cannabinoids in pain. It comprehensively covers the current challenges with medical cannabis utilization and provides recommendations for research and future directions. Organized into nine sections, the book begins with an introduction to medical cannabis, including its history, regulations, and the general attitudes of pain physicians on cannabis. Section two explores the biological effects of marijuana via the endocannabinoid system and its complex structure of receptors and enzymes. Sections three, four, and five then delve further into pharmacology and the mechanisms of action applicable to cannabinoids in managing pain. Timely and socially conscious, section six examines the benefits of substituting opioids with cannabinoids for preoperative management. Echoing the book's well-rounded content, sections seven and eight consider the challenges with medical cannabis, including safety and quality control, brain development risks, vaping hazards, and withdrawal. The book then closes with a look at the future of cannabis in medical research. Thoroughly and equitably composed, Cannabinoids and Pain is an invaluable resource for primary care physicians, pain and palliative care physicians, and oncologists.
Book Synopsis Cannabinoids and Their Receptors by :
Download or read book Cannabinoids and Their Receptors written by and published by Academic Press. This book was released on 2017-07-24 with total page 562 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cannabinoids and Their Receptors, Volume 593, the latest release in the Methods in Enzymology series, continues the legacy of this premier serial with quality chapters authored by leaders in the field. This updated volume includes comprehensive chapters on a variety of topics, including Real time cAMP signaling in response to CB1 activation, CB1 signaling in mitochondria, Lipidomics of cannabinoid systems, Studying endocannabinoid transport, Metabolic profiling of CB1 neutral antagonists, Approaches to assess biased signaling at the CB1 receptor, and the Development of CB1 allosteric modulators. Continues the legacy of this premier serial with a new and updated release Covers research cannabinoids and their receptors
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 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 The Cannabinoid Receptors by : Patricia H. Reggio
Download or read book The Cannabinoid Receptors written by Patricia H. Reggio and published by Springer Science & Business Media. This book was released on 2008-11-09 with total page 407 pages. Available in PDF, EPUB and Kindle. Book excerpt: As research has progressed, the cannabinoid CB 1 and CB 2 receptors have expanded significantly in importance within the neuroscience mainstream. In The Cannabinoid Receptors, leading experts introduce newcomers to the cannabinoid field with chapters covering cannabinoid ligand synthesis and structure activity relationships, the molecular pharmacology of the cannabinoid receptors and the endocannabinoid system, and ultimately, the whole animal pharmacology and therapeutic applications for cannabinoid drugs. Adding to those key topics, the book also examines the current direction of the field with chapters on new putative cannabinoid receptors and challenges for future research. As a part of The Receptors TM series, this volume highlights its receptor with the most thorough, focused and essential information available. Comprehensive and cutting-edge, The Cannabinoid Receptors serves as an ideal guidebook to what continues to be a fascinating and vital field.
Book Synopsis Cannabis Therapy in Veterinary Medicine by : Stephen Cital
Download or read book Cannabis Therapy in Veterinary Medicine written by Stephen Cital and published by Springer Nature. This book was released on 2021-05-16 with total page 343 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book provides in-depth information on the applications of cannabis products as a legitimate medicine in treating a variety of diseases and disorders in domestic animals. Pharmacology and toxicology of cannabinoids and their effects on the endocannabinoid system, which is involved in the regulation of diverse physiological and cognitive processes, are discussed in detail. Furthermore, the book reviews development and testing of cannabis based medical products and introduces the nutritional components of cannabis plants. Cannabis as a therapeutic in veterinary medicine is gaining interest among owners and practitioners. Numerous studies have been completed or are currently underway that analyze the potential of clinical application of cannabinoid and terpenoid molecules. In this book the authors take a comprehensive look at previous studies in animal and human models and discuss translational applications based on these scientific data. This seminal text serves as a go-to resource for veterinary practitioners on cannabinoid therapy. It will also serve as a foundation for clinicians and researchers interested in this emerging field of veterinary medicine.
Book Synopsis Cannabinoids and Sleep by : Jaime M. Monti
Download or read book Cannabinoids and Sleep written by Jaime M. Monti and published by Springer Nature. This book was released on 2021-02-03 with total page 194 pages. Available in PDF, EPUB and Kindle. Book excerpt: Research on cannabis and sleep is emerging with promising results. This book offers current and comprehensive knowledge on cannabinoid research results in connection with sleep. The volume covers aspects of the hemp plant Cannabis sativa, the pharmacology of cannabinoids, neurobiology and pharmacology of sleep and wakefulness, and the benefits and side effects of cannabis on the central nervous system. It further discusses the putative therapeutical properties of cannabinoids and endocannabinoids and their potential for the treatment of sleep disorders such as insomnia, obstructive sleep apnea, REM sleep behavior disorder, and restless legs syndrome. The book is written by medical and scientific experts in this field and intended for researchers from a range of disciplines such as biomedicine, biology, neurosciences, clinical medicine, neurology, and pharmacology.
Book Synopsis Medicinal Cannabis and CBD in Mental Healthcare by : Kylie O'Brien
Download or read book Medicinal Cannabis and CBD in Mental Healthcare written by Kylie O'Brien and published by Springer Nature. This book was released on 2021-10-27 with total page 591 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book functions as a clinician’s guide to the use of cannabidiol (CBD) in the treatment of mental health conditions. It conveys the scientific evidence of efficacy of CBD as well as THC and addresses the social stigma attached to its medical use. The book describes the endocannabinoid system, how stress and the endocannabinoid system interact and key constituents, pharmacokinetics and safety aspects of medicinal cannabis, focusing on CBD and THC. Chapters on specific mental health conditions describe the underpinning pathomechanisms including how the endocannabinoid system is involved, and summarises the scientific evidence including animal and human research for the use of CBD and THC in treatment of such conditions. Topics covered include anxiety, depression, post-traumatic stress disorder, insomnia, Alzheimer's Disease and autism spectrum disorder. Chapters also discuss treatment guidelines and case studies. Unique and focused, Medicinal Cannabis and CBD in Mental Healthcare is an invaluable reference for medical practitioners seeking to adopt CBD-use in their treatment plans.
Book Synopsis Textbook of Receptor Pharmacology by : John C. Foreman
Download or read book Textbook of Receptor Pharmacology written by John C. Foreman and published by CRC Press. This book was released on 2010-09-10 with total page 314 pages. Available in PDF, EPUB and Kindle. Book excerpt: For the past four decades, University College London has offered a renowned course on receptor pharmacology. Originating from this course, the perennially bestselling Textbook of Receptor Pharmacology has presented in-depth coverage of this rapidly expanding area of research. This third edition continues to combine current understanding of classica
