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Structure Function Studies Of Nicotinic Acetylcholine Receptors Using Selective Agonists And Positive Allosteric Modulators
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Book Synopsis Structure-function Studies of Nicotinic Acetylcholine Receptors Using Selective Agonists and Positive Allosteric Modulators by : Christopher Bruno Marotta
Download or read book Structure-function Studies of Nicotinic Acetylcholine Receptors Using Selective Agonists and Positive Allosteric Modulators written by Christopher Bruno Marotta and published by . This book was released on 2015 with total page 278 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Structure-function Studies of Nicotinic Acetylcholine Receptors Using Unnatural Amino Acids and Synthetic Agonist Analogs by : Angela Patricia Blum
Download or read book Structure-function Studies of Nicotinic Acetylcholine Receptors Using Unnatural Amino Acids and Synthetic Agonist Analogs written by Angela Patricia Blum and published by . This book was released on 2012 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Pharmacological and Structure-function Studies of M1 Muscarinic Acetylcholine Receptor Allosteric Modulation by : Alaa Abdul-Ridha
Download or read book Pharmacological and Structure-function Studies of M1 Muscarinic Acetylcholine Receptor Allosteric Modulation written by Alaa Abdul-Ridha and published by . This book was released on 2015 with total page 428 pages. Available in PDF, EPUB and Kindle. Book excerpt: The M1 muscarinic acetylcholine receptor (mAChR) is predominantly expressed in the brain where it plays a major role in mediating cognitive processes such as learning and memory. As a result, it has been implicated in diseases where such processes are impaired, such as Alzheimer's disease and schizophrenia. Drug discovery efforts aimed at developing selective ligands for this receptor, both as therapeutics and as experimental tools, have largely failed as they focused on targeting the acetylcholine (ACh) binding site, which is identical in all five mAChR subtypes. The discovery of benzyl quinolone carboxylic acid (BQCA), the first positive allosteric modulator (PAM) with high selectivity for the M1 mAChR, has lead to a renaissance in selective targeting of this receptor family.In chapter 2 we exploit the unique "two-state" pharmacology of BQCA to investigate allosteric modulation at a chemogenetically modified M1 mAChR, developed as an alternative means to achieve selective receptor targeting in vivo. This study demonstrates that such an approach may not be valid, as chemogenetic modification of the M1 mAChR leads to changes in the allosteric behaviour of BQCA that are not reminiscent of its behaviour at the native receptor. As a consequence, caution must be exercised when interpreting studies of allosteric modulation using chemogenetically modified receptors in vivo.Despite the unique pharmacology of BQCA, the molecular mechanisms of its binding and function and the structural basis of its M1 mAChR selectivity remain poorly defined. Such knowledge would enable the design of novel M1 mAChR PAMs with improved pharmacological profiles. Chapters 3 and 4 comprise studies focussed on identifying the amino acid residues that form the allosteric binding pocket at the M1 mAChR and/or play a role, either directly or indirectly, in the transmission of cooperativity with the orthosteric (ACh) binding site. Deeper mechanistic insights into allosteric modulation at the M1 mAChR are further afforded by the use of benzoquinazolinone 12, a high affinity structural derivative of BQCA. The experimental findings are contextualised using molecular models, and collectively, the results suggest that many of the key residues that form the allosteric binding pocket at the M1 mAChR are structurally conserved in other mAChR subtypes. The findings in this thesis challenge the common assumption that allosteric ligands achieve subtype selectivity through binding to allosteric sites that are less conserved between subtypes and propose that the selectivity of BQCA and benzoquinazolinone 12 arises from selective cooperativity with ACh at the M1 mAChR. The information herein may guide the rational design of M1 mAChR positive and/or negative allosteric ligands with increased therapeutic potential.
Book Synopsis Structure-function Studies of M4 Muscarinic Acetylcholine Receptor Allosteric Modulation by : Oshadhi Vindhya Nawaratne
Download or read book Structure-function Studies of M4 Muscarinic Acetylcholine Receptor Allosteric Modulation written by Oshadhi Vindhya Nawaratne and published by . This book was released on 2011 with total page 356 pages. Available in PDF, EPUB and Kindle. Book excerpt: The M4 muscarinic acetylcholine receptor (mAChR) is implicated in many central nervous system disorders, however, due to a highly conserved acetylcholine (ACh) binding orthosteric site, there is a lack of highly selective ligands as therapeutics and experimental probes for this target. There are two classes of functionally selective M4 mAChR ligands, one being the allosteric modulators, typified by the small molecule LY2033298 (3-amino-5-chloro-6-methoxy-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide) (Chan et al., 2008), and the other being the atypical agonists, exemplified by xanomeline and McN-A-343, whose mode of binding at the M4 mAChR is not clear. Challenges to understanding the activity of these ligands include the interplay of binding, efficacy and, when considering allosteric modulation, cooperativity. Thus, to investigate the molecular determinants of allosteric and atypical agonist activity, site-directed mutagenesis was utilised in conjunction with radioligand assays, to determine the role of specific amino acid residues on affinity or binding cooperativity, and M4 mAChR-mediated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, as a measure of efficacy or functional modulation by LY2033298. The endogenous agonist, ACh was used as a control agonist.Chapter 2 focused on four different regions of the M4 mAChR; extracellular loops (ECLs) 1, 2 and 3, and transmembrane domain (TM) 7. In the ECL1, we identified Ile93(2.65) and Lys95(2.67) as key residues that specifically governed the signalling efficacy of LY2033298 and its binding cooperativity with ACh, while Phe186(5.29) in the ECL2 was identified as a key contributor to the binding affinity of the modulator for the allosteric site. The highly conserved TM7 residues, Tyr439(7.39) and Tyr443(7.43), were important for both McN-A-343 and xanomeline affinity, while the ECL residues, Ile93(2.65), Phe186(5.29), Ser428(6.63) and Asp432(7.32) were detrimental to McN-A-343 affinity. Ser428(6.63) was exclusively involved in atypical agonist efficacy. In contrast, Tyr439(7.39) and Tyr443(7.43), were identified as contributing to a key activation switch utilized by all classes of agonists, except xanomeline. This initial study highlighted the general importance of aromatic residues for allosteric agonist activity, which led us to perform alanine scanning mutagenesis of selected aromatic residues in the top third the M4 mAChR. Additionally, due to the importance of Phe186(5.29) in allosteric agonist binding in the ECL2, residues lining the proximal and distal ends of ECL2 was also mutated. Results outlined in Chapter 3 showed that, Tyr89(2.61) and Trp435(7.35), on top of TM2 and TM7, respectively, were important for LY2033298 binding. Tyr89(2.61) was exclusively involved in LY2033298 efficacy compared to the other ligands, while other TM2/ECL1 residues also played a large role in LY2033298 efficacy. Multiple residues clustered between the putative allosteric and orthosteric sites, on TM2/ECL1 and TM7, appear to form the conformational link for transmitting ACh-LY2033298 cooperativity. Tyr89(2.61) was particularly important for the positive binding cooperativity between ACh and LY2033298. Only two residues (Tyr89(2.61) and Tyr439(7.39)) were identified to affect the functional modulation of ACh by LY2033298 in the current thesis. Orthosteric binding site residues, Trp164(4.57) and Trp413(6.48), were global activation switches for both allosteric and orthosteric agonists.The final study, outlined in Chapter 4, characterised the activity of the atypical agonists at the second set of mutant M4 mAChRs. It revealed that Trp413(6.48) is a critical contact residue for xanomeline, while playing a smaller role in ACh and McN-A-343 binding. In the distal ECL2, Ile187(5.30), may play a role in both xanomeline and McN-A-343 binding, while Ile187(5.30), Gln188(5.31) and Phe189(5.32) played a large role in McN-A-343 efficacy. Trp164(4.57) and Trp413(6.48), like Tyr439(7.39) and Tyr443(7.43), were global activation switches for all three classes of agonists. These results provide new insights into the existence of multiple binding pockets and activation switches in G protein-coupled receptors (GPCRs), some of which can be selectively exploited by allosteric and atypical agonists for future development of selective M4 mAChR ligands, whereas others represent global activation mechanisms for all classes of ligand.
Book Synopsis Structure-function Studies of Nicotinic Acetylcholine Receptors Using Unnatural Amino Acids by : Nyssa Leigh Puskar
Download or read book Structure-function Studies of Nicotinic Acetylcholine Receptors Using Unnatural Amino Acids written by Nyssa Leigh Puskar and published by . This book was released on 2012 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Positive Allosteric Modulators of Alpha4beta2 Neuronal Nicotinic Acetylcholine Receptors by : Atul Dilip Jain
Download or read book Positive Allosteric Modulators of Alpha4beta2 Neuronal Nicotinic Acetylcholine Receptors written by Atul Dilip Jain and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Des-Formylflustrabromine (dFBr), isolated from the marine organism Flustra foliacea, is the first selective, positive allosteric modulator (PAM) of [alpha]4[beta]2 nicotinic acetylcholine receptors that potentiates the action of the neurotransmitter acetylcholine (ACh). Most agonists for this receptor population are not selective and can activate other nACh receptors. A selective PAM, which activates [alpha]4[beta]2 nACh receptors only in the presence of ACh, might find application in the treatment of of various neurological diseases such as Alzheimer's disease or autism. dFBr was examined and found to produce a biphasic dose-response curve over a wide concentration range (i.e., potentiation at low concentration, but inhibition of the ACh-induced response at high concentrations). Our goal was to examine various structural features of dFBr required for potentiation; a secondary goal was to examine the same for inhibition. To understand the structural requirements of dFBr, a systematic 'deconstruction reconstruction and elaboration' approach (see p. 48) was employed to determine the contribution of various structural components of dFBr to its activity at [alpha]4[beta]2 nACh receptors. Novel compounds were synthesized and characterized. Human [alpha]4[beta]2 nACh receptors were expressed in Xenopus oocytes and the actions of dFBr and its analogs were measured using a two-electrode voltage clamp technique. Dose-response curves were obtained for the compounds in the absence and presence of 100 [micro]M ACh. Structural features of dFBr optimal and/or required for PAM action at a4b2 nACh receptors were identified. A novel reconstructed analog with all the essential features for PAM action was synthesized and submitted for biological testing. Elaborated analogs of dFBr further helped in identification of various structural features important for PAM action and the inhibition of action of ACh. The 'deconstruction reconstruction and elaboration' approach (see p.48) identified important structural features of dFBr that modify its actions as a PAM or an antagonist (NAM? or channel blocker?) at [alpha]4[beta]2 nACh receptors. This information should be useful for the subsequent design of novel analogs to evaluate their potential for the treatment of neurological disorders associated with ACh.
Book Synopsis Cellular and Molecular Neurophysiology by : Constance Hammond
Download or read book Cellular and Molecular Neurophysiology written by Constance Hammond and published by Elsevier. This book was released on 2024-06-03 with total page 602 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cellular and Molecular Neurophysiology, Fifth Edition is the only up-to-date textbook on the market that focuses on the molecular and cellular physiology of neurons and synapses. Hypothesis-driven rather than a dry presentation of the facts, the book promotes a real understanding of the function of nerve cells that is useful for practicing neurophysiologists and students in graduate-level courses on the topic alike. This new edition explains the molecular properties and functions of excitable cells in detail and teaches students how to construct and conduct intelligent research experiments. The content is firmly based on numerous experiments performed by top experts in the field. The new edition contains new chapters on recording neuronal activity, iconotrophic and metabotropic receptors for sensory transduction, and a section containing exercises for further learning. This book will be a useful resource for neurophysiologists, neurobiologists, neurologists, and students taking graduate-level courses on neurophysiology. Authoritative foundational coverage of basic cellular and molecular neurophysiology Includes new chapters on recording neuronal activity, iconotrophic and metabotropic receptors for sensory transduction Provides fifteen appendices that describe how neurobiological techniques are interspersed in the text Presents enhanced coverage of new methodologies and experimental techniques
Book Synopsis Nicotinic Acetylcholine Receptor by : Alfred Maelicke
Download or read book Nicotinic Acetylcholine Receptor written by Alfred Maelicke and published by Springer Science & Business Media. This book was released on 2013-06-29 with total page 489 pages. Available in PDF, EPUB and Kindle. Book excerpt: Proceedings of the NATO Advanced Research Workshop on Mechanism of Action of the Nicotinic Acetylcholine Receptors held on the Island of Santorini, Greece, May 19-23, 1986
Book Synopsis Hemoglobin and Myoglobin in Their Reactions with Ligands by : Eraldo Antonini
Download or read book Hemoglobin and Myoglobin in Their Reactions with Ligands written by Eraldo Antonini and published by North-Holland. This book was released on 1971 with total page 464 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Tobacco Alkaloids written by Amé Pictet and published by . This book was released on 1904 with total page 14 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Neuronal Nicotinic Receptors by : F. Clementi
Download or read book Neuronal Nicotinic Receptors written by F. Clementi and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 837 pages. Available in PDF, EPUB and Kindle. Book excerpt: Neuronal nicotinic receptors are key molecules for signal transduction in a number of neuronal pathways. They are widely distributed in the brain and are known to be involved in cognitive tasks, including learning and memory, in smoking addiction and in several brain diseases, such as Alzheimer's and Parkinson's dementias, schizophrenia, and epilepsy. This book provides a comprehensive review of the field, starting with a historical perspective and dealing with the molecular structure of these receptors, their biophysical and pharmacological properties, their distribution in central and peripheral nervous systems, and their major involvement in brain functions. Particular emphasis is paid to drugs (both new and old) that are useful in the diagnosis and treatment of diseases involving neuronal nicotinic receptors. Finally, the relevance of these receptors in smoking addiction is carefully evaluated, together with future trends and the latest results.
Book Synopsis Cholinergic Mechanisms by : Peter Gaudenz Waser
Download or read book Cholinergic Mechanisms written by Peter Gaudenz Waser and published by . This book was released on 1975 with total page 586 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Pathy's Principles and Practice of Geriatric Medicine by : Alan J. Sinclair
Download or read book Pathy's Principles and Practice of Geriatric Medicine written by Alan J. Sinclair and published by John Wiley & Sons. This book was released on 2012-03-13 with total page 3453 pages. Available in PDF, EPUB and Kindle. Book excerpt: This new edition of the comprehensive and renowned textbook Principles and Practice of Geriatric Medicine offers a fully revised and updated review of geriatric medicine. It covers the full spectrum of the subject, features 41 new chapters, and provides up-to-date, evidence-based, and practical information about the varied medical problems of ageing citizens. The three editors, from UK, USA and France, have ensured that updated chapters provide a global perspective of geriatric medicine, as well as reflect the changes in treatment options and medical conditions which have emerged since publication of the 4th edition in 2006. The book includes expanded sections on acute stroke, dementia, cardiovascular disease, and respiratory diseases, and features a new section on end-of-life care. In the tradition of previous editions, this all-encompassing text continues to be a must-have text for all clinicians who deal with older people, particularly geriatric medical specialists, gerontologists, researchers, and general practitioners. This title is also available as a mobile App from MedHand Mobile Libraries. Buy it now from Google Play or the MedHand Store. Praise for the 4th edition: "...an excellent reference for learners at all clinical and preclinical levels and a useful contribution to the geriatric medical literature." —Journal of the American Medical Association, November 2006 5th edition selected for 2012 Edition of Doody's Core TitlesTM
Book Synopsis Voltage Gated Sodium Channels by : Peter C. Ruben
Download or read book Voltage Gated Sodium Channels written by Peter C. Ruben and published by Springer Science & Business Media. This book was released on 2014-04-15 with total page 328 pages. Available in PDF, EPUB and Kindle. Book excerpt: A number of techniques to study ion channels have been developed since the electrical basis of excitability was first discovered. Ion channel biophysicists have at their disposal a rich and ever-growing array of instruments and reagents to explore the biophysical and structural basis of sodium channel behavior. Armed with these tools, researchers have made increasingly dramatic discoveries about sodium channels, culminating most recently in crystal structures of voltage-gated sodium channels from bacteria. These structures, along with those from other channels, give unprecedented insight into the structural basis of sodium channel function. This volume of the Handbook of Experimental Pharmacology will explore sodium channels from the perspectives of their biophysical behavior, their structure, the drugs and toxins with which they are known to interact, acquired and inherited diseases that affect sodium channels and the techniques with which their biophysical and structural properties are studied.
Book Synopsis Ion Channel Pharmacology by : Bernat Soria
Download or read book Ion Channel Pharmacology written by Bernat Soria and published by . This book was released on 1998 with total page 498 pages. Available in PDF, EPUB and Kindle. Book excerpt: The improved understanding of ion channel structure, achieved through the use of molecular biology techniques, has opened the way for the development of new drugs targeted at specific types of ion channels. This book provides a comprehensive, single-volume overview of the effects of different drugs and toxins on ionic channels. The first part of the book deals with the development of ion channels, while subsequent chapters detail the electrophysiological properties and pharmacology of eight different types of ion channels, including intracellular, cyclic nucleotide-gated, and receptor operated channels. Drug effects in various cell types, along with the potential use of channels in therapeutics, are discussed for each channel type. Comprehensive and up-to-date, Ion Channel Pharmacology is an essential reference for every investigator in this fast-growing area of research.
Author :United States. Public Health Service. Office of the Surgeon General Publisher : ISBN 13 : Total Pages :728 pages Book Rating :4.:/5 (318 download)
Book Synopsis How Tobacco Smoke Causes Disease by : United States. Public Health Service. Office of the Surgeon General
Download or read book How Tobacco Smoke Causes Disease written by United States. Public Health Service. Office of the Surgeon General and published by . This book was released on 2010 with total page 728 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.
Book Synopsis Anesthetic Pharmacology by : Alex S. Evers
Download or read book Anesthetic Pharmacology written by Alex S. Evers and published by Cambridge University Press. This book was released on 2011-03-10 with total page 2902 pages. Available in PDF, EPUB and Kindle. Book excerpt: In recent years our understanding of molecular mechanisms of drug action and interindividual variability in drug response has grown enormously. Meanwhile, the practice of anesthesiology has expanded to the preoperative environment and numerous locations outside the OR. Anesthetic Pharmacology: Basic Principles and Clinical Practice, 2nd edition, is an outstanding therapeutic resource in anesthesia and critical care: Section 1 introduces the principles of drug action, Section 2 presents the molecular, cellular and integrated physiology of the target organ/functional system and Section 3 reviews the pharmacology and toxicology of anesthetic drugs. The new Section 4, Therapeutics of Clinical Practice, provides integrated and comparative pharmacology and the practical application of drugs in daily clinical practice. Edited by three highly acclaimed academic anesthetic pharmacologists, with contributions from an international team of experts, and illustrated in full colour, this is a sophisticated, user-friendly resource for all practitioners providing care in the perioperative period.
