In Order to Read Online or Download Allosteric Modulation Of G Protein Coupled Receptors Full eBooks in PDF, EPUB, Tuebl and Mobi you need to create a Free account. Get any books you like and read everywhere you want. Fast Download Speed ~ Commercial & Ad Free. We cannot guarantee that every book is in the library!
Book Description :
Download Allosteric Modulation of G Protein coupled Receptors book written by Lauren Therese May, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.
Book Description :
Download Allosteric Modulation of G Protein coupled Receptors book written by Zhan-Guo Gao, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.
Book Description :
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
Book Description :
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
Book Description :
Download Allosteric Modulation of G Protein coupled Receptors book written by Joaquin Botta, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.
Book Description :
Allosteric Modulation of G Protein-Coupled Receptors reviews fundamental information on G protein-coupled receptors (GPCRs) allosteric modulation and presents original research in the area, which collectively provides a comprehensive description of the key issues in GPCR allosteric modulation. 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 signalling at a site apart from the endogenous ligand. Recent methodological and analytical advances have greatly improved our ability to understand the signalling 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. Allosteric modulation, whether through small molecules, peptides, or protein-protein interactions, represents a novel and enticing means of affecting GPCR function. But, it is not without its challenges. This 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. Allosteric Modulation of G Protein-Coupled Receptors is an essential book for researchers and advanced students engaged in pharmacology, toxicology, and pharmaceutical sciences training and research Introduces background on core concepts of molecular pharmacology: 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, 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 Description :
Download Allosteric Modulation by Sodium Ions and Amilorides of G Protein coupled Receptors book written by , available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.
Book Description :
"G protein coupled receptors (GPCR) represent over 30% of drug targets and are involved in nearly all physiological and cellular responses. The angiotensin II (AngII) type I receptor (AT1R) is an important member of this receptor family. Its main endogenous ligand is the hormone angiotensin II (AngII), which regulates blood volume and vascular resistance, through the renin-angiotensin system (RAS). This hormone is involved in hypertension and other cardiovascular diseases. A way to improve today's therapeutic approach is to aim for the activation of the beneficial cellular responses without activating the ones responsible for undesirable effects. This type of response can be achieved using ligands that show functional selectivity, also known as biased signaling. This type of ligand imposes distinct conformations to the receptor, therefore promoting selective downstream effector activation. Moreover, our lab has recently shown that functional selectivity was possible using an allosteric modulator (a ligand binding to any site on a GPCR that is topographically distinct from the endogenous binding site). Our group has shown that a peptide mimic of a sequence derived from the second extracellular loop (ECL2) domains of the prostaglandin F2[alpha] (PGF2[alpha]) receptor (FP) acted as a biased-allosteric modulator of FP. We hypothesized that the ECL2 of other GPCRs can be used as putative biased-allosteric modulators. To test this, we used the angiotensin II (AngII) type I receptor (AT1R). We have examined the effects of peptides (SC0023/SC0024) derived from AT1R's ECL2 in vascular smooth muscle cells (VSMC). This was done using techniques including western blots, Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) and [3H]-Thymidine incorporation. We show in VSMCs that the SC0023 peptide decreases angiotensin II-induced ERK1/2 activation and inositol monophosphate (IP1) production, thus acting as a negative allosteric modulator (NAM) on these signaling pathways. Conversely, SC0024 has no effect on ERK1/2 while acting as a positive allosteric modulator (PAM) on IP1 production. Interestingly, the SC0023 peptide showed no modulatory effect on proliferation in response to angiotensin II, whereas the SC0024 peptide inhibited almost completely this response, hence acting as a NAM on AngII-mediated proliferation. In addition, structure-function studies underscored the importance of three residues (Phe-His-Tyr) of peptide SC0024 for its NAM effect on proliferation. More importantly, these peptides alone showed no effect on any of the pathways studied, thus only working in the presence of agonist, which is characteristic of most allosteric modulators. These data imply that these two peptides derived from the ECL of AT1R are allosteric modulators with biased signaling properties. Indeed, SC0023 acts as a NAM of ERK1/2 activation and IP1 production, while SC0024 acts as a PAM of IP1 production and a NAM of proliferation. Ultimately, understanding how the ECL2 is allosterically biasing its receptor will allow us to design new and more efficient therapeutics." --
Book Description :
"G protein-coupled receptors (GPCRs) comprise the largest group of cell surface receptors, translating environmental signals into cellular responses via cognate G protein partners. Contrary to our initial understanding, most GPCRs do not function in living cells as monomers, but most likely dimers, or even larger arrays of receptors. Standard drug design approaches rely on the notion that drugs binding the two receptors in a given dimer likely function independently of one another. However, this view has been challenged by recent work showing that ligand binding at both receptors can modulate dimeric receptors via allosteric communication. While one receptor may actually be needed to drive signalling, the other acts to control or modulate these signals, without a direct signalling outcome itself. Based on the notion of allosteric modulation within homo- and heterodimers, I tested and compared changes in signalling downstream as well as at the level of the receptor-G protein-effector (RGE) complex in response to different combinations of ligands at each protomer. Using a combination of calcium, cyclic adenosine monophosphate, and mitogen-activated protein kinase signalling assays, I have demonstrated functional interactions for a putative D2 dopamine receptor, oxytocin receptor heterodimer (D2R/OTR), in HEK 293 cells. Immunoprecipitation, bioluminescence resonance energy transfer (BRET) and confocal microscopy experiments reveal D2R and OTR do in fact form a heterodimer in vitro, which may explain the nature of these potential allosteric functional interactions. Using BRET, I assessed the RGE complex conformational dynamics in HEK 293 cells for two other heterodimers, [beta]2-adrenergic receptor with cannabinoid CB1 receptor ([beta]2AR/CB1R) and [beta]2AR/OTR, in order to determine how they manifest in parallel to signalling events themselves. These studies reveal functional interactions can occur in terms of signalling complex conformation. Thus GPCR signalling can be modulated by its partner receptor at the level of downstream effector signalling or at the level of the signalling complex itself. With that said, putative heterodimers need to be reanalyzed in vivo for their allosteric properties, which may explain some of the side effects of so many drugs, and may have implications in drug design." --
Book Description :
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
Book Description :
G protein coupled receptors remain the most important class of therapeutic targets in medicine. In the last 5 years, tremendous advances have been made in our understanding of the structure and mechanism of this critical family of drug targets. The present volume explores the modern experimental and conceptual framework for drug discovery for G protein coupled receptors. It explores advances in structure determination and structure-based drug design as well as new concepts of allosteric modulation, functional selectivity/biased agonism, and pharmacological chaperones. In addition, emerging drug targets such as receptor families for fatty acids, carboxylic acids, lipid mediators, etc. are included. Final chapters cover novel mechanisms of signal regulation through PDZ domains and RGS proteins. This volume will bring an up-to-date perspective on the G protein coupled receptor field to both academic and industry scientists. The present volume explores the modern experimental and conceptual framework for drug discovery for G protein coupled receptors It explores advances in structure determination and structure-based drug design as well as new concepts of allosteric modulation, functional selectivity/biased agonism, and pharmacological chaperones This volume will bring an up-to-date perspective on the G protein coupled receptor field to both academic and industry scientists
Book Description :
"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 Description :
Download Modulation of Cannabinoid Receptor Activity by Allosteric Modulators Inverse Agonists and Receptor Binding Partners book written by Mariam Mohammed Mahmoud, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.
Book Description :
Download Structural Studies of the Interaction Between MGlu5 and Allosteric Modulators book written by Elizabeth Dong Nguyen, available in PDF, EPUB, and Kindle, or read full book online anywhere and anytime. Compatible with any devices.
Book Description :
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 Description :
The interaction of a drug with a receptor generates a code of information having components of affinity and efficacy. How this information is translated into a response depends on the unique cells, tissue, organ or system in which the receptor resides. This book describes how to analyze various responses to estimate the affinity and efficacy components of the initial drug–receptor interaction. More specifically, it describes how to measure the affinity and efficacy of drugs through the analysis of single receptor activity, the activation state of a population of receptors, and responses downstream from receptor activation. More light is thrown on ligand-gated ion channels and G protein-coupled receptors in this book. The topics discussed include radioligand binding, estimation of agonist affinity and efficacy, competitive antagonism, inverse agonism, allosteric agonists and modulators, agonist bias, modulation of pathway selectivity, and the estimation of ligand affinity for active and inactive receptor states. The natural history and structure of ligand-gated ion channels, G proteins, and G protein-coupled receptors are also discussed. Contents:Ligand-Gated Ion Channels:Ligand-Gated Ion ChannelsAffinity and Efficacy of Orthosteric Ligands at Ligand-Gated Ion ChannelsCompetitive Interactions Between Orthostheric Ligands at Ligand-Gated Ion ChannelsAnalysis of Allosteric Interactions at Ligand-Gated Ion ChannelsG Protein-Coupled Receptors:G Protein-Coupled Receptors and G Protein and Arrestin SignalingAffinity and Efficacy of the Agonist-Receptor-G-Protein InteractionEstimating Affinity and Efficacy by Reverse-Engineering the Response-Clamp AnalysisAnalysis of Agonism and Inverse Agonism in Signaling Pathways that Exhibit Constitutive ActivityAnalysis of Ligand Bias in Receptor Signaling through Different G Protein PathwaysCompetitive Interactions Between Orthosteric Ligands in Functional Assays on G Protein-Coupled ReceptorsAnalysis of Allosterism in Functional Assays on G Protein-coupled ReceptorsRadioligand Binding:Analysis of Drug-receptor Interactions Using Radioligand Binding Assays on G Protein-coupled Receptors Readership: Postgraduates and researchers in pharmacology and physiology, professionals in the pharmaceutical industry, neuroscience researchers. Key Features:The concepts of receptor theory and hierarchical levels of pharmacological analysis are integrated and emphasised throughout the bookStep-by-step instructions are given for the different types of pharmacological analysesKeywords:Affinity;Efficacy;Drug-Receptor Interactions;Agonism;Antagonism;Allosterism;Binding;Ligand Directed Signaling;Pathway Selectivity;Inverse Agonism;G Protein-Coupled Receptors;Ligand-Gated Ion Channels;Cell Signaling
Book Description :
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. Addresses our current understanding and novel advances in the GPCR field, directing readers towards recent finding of key significance for translational medicine Combines a thorough discussion of structure and function of GPCRs with disease association and drug discovery Features chapter contributions from international experts in GPCR structure, signaling, physiology and pharmacology
Book Description :
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of insulin biosynthesis and secretion, and is one of the key therapeutic targets in the management of type II diabetes mellitus and obesity. Like most GPCRs, the GLP-1R is pleiotropically coupled, to physiologically relevant signalling pathways including cAMP formation, intracellular calcium (iCa2+) mobilization and phosphorylation of extracellular signal regulated kinases 1 and 2 (pERK1/2). The GLP-1R is a class B G protein-coupled receptor (GPCR) that has the ability to be activated by multiple endogenous ligands including four variants of GLP-1 (the predominant form being GLP-1(7-36)NH2) and oxyntomodulin. This receptor is also activated by the exogenous peptide exendin-4 and allosteric ligands such as the Novo Nordisk Compound 2 and Eli Lily 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP). These allosteric ligands also have unique properties compared to orthosteric exogenous ligands including the ability to alter the signalling of the GLP-1R in response to orthosteric ligands. These effects can be different depending on which orthosteric ligand is co bound to the receptor, a effect known as probe-dependence. This thesis identifies a novel case of probe dependence, the ability of allosteric ligands to modify the signalling mediated by metabolites of endogenous ligands that were previously considered to be 'inert' breakdown products that may open up new avenues for allosteric drug discovery.It is widely accepted that insulin secretion downstream of GLP-1R activation is critically dependent on cAMP formation, but recent evidence is also emerging for an essential role of regulatory proteins such as [beta]-arrestins and G protein-coupled receptor kinases (GRK). The canonical role of these regulatory proteins is to terminate GPCR signalling and promote receptor internalization. However, more recently, roles as scaffolding proteins that can regulate G protein-independent signalling have emerged. Consequently, the studies comprising this thesis illustrate distinct recruitment profiles of regulatory proteins to the GLP-1R in response to multiple endogenous and exogenous ligands. This thesis identifies differential actions of allosteric modulators on GLP-1R peptide ligands ('probe dependence'), thus demonstrating differential responses of receptor signalling with respect to both orthosteric and allosteric ligands, highlighting the ability for both ligand- and pathway-specific effects ('biased signalling'). Collectively, this work further demonstrates the potential benefits of biased signalling and allosteric modulation, but may also influence the approaches and precautions that must be considered in the design, identification and development of small molecules for therapeutic use.
Book Description :
Bioactive compounds from Cannabis sativa have been used for millennia to alleviate the symptoms of a range of diseases. The physiological basis of effects such as analgesia, stimulation of hunger and reduction of inflammation was established in the late 20th century with the discovery of cannabinoid receptors but efforts to synthesise safe and potent drugs targeting these proteins have so far failed. The major barrier to research in this area is the instability of the receptors outside of biological settings, rendering elucidation of the binding sites by traditional means difficult. Certain small molecules can interact with the cannabinoid type 1 receptor (CB1) at locations distinct to the primary ligand docking site. Such allosteric modulation of the endocannabinoid system offers significant advantages over using orthosteric drugs and in this research a range of indole based structures were synthesised and tested in an attempt to improve the activity and drug-like nature of a lead compound. A partial structure-activity relationship was established, including the description of the most potent allosteric enhancer of CB1 so far reported. Efforts were also undertaken to investigate the allosteric binding environments using photoactivatable ligands based on a CB1 inhibitor. In combination with mutation studies and computer modelling this technique could allow the rational design of allosteric modulators, a task which is not trivial at present. Two photoactivatable compounds were synthesised and shown to interact with the receptor, with a method for isolating covalently labelled peptide fragments from other biomolecules demonstrated using "click chemistry" and a modified Wang resin. This work may find application in future investigations aiming to produce allosteric pharmaceuticals targeting CB1. Furthermore, the techniques described may be applied to study the binding site of a recently described allosteric endocannabinoid or could potentially be adapted to look at secondary binding domains in other G protein-coupled receptors.
Book Description :
G protein-coupled receptors (GPCRs) are one of the most important target classes in pharmacology and are the target of many blockbuster drugs. Yet only with the recent elucidation of the rhodopsin structure have these receptors become amenable to a rational drug design. Based on recent examples from academia and the pharmaceutical industry, this book demonstrates how to apply the whole range of bioinformatics, chemoinformatics and molecular modeling tools to the rational design of novel drugs targeting GPCRs. Essential reading for medicinal chemists and drug designers working with this largest class of drug targets in the human genome.