The Experts below are selected from a list of 47301 Experts worldwide ranked by ideXlab platform
Bryan L. Roth - One of the best experts on this subject based on the ideXlab platform.
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Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists.
Journal of medicinal chemistry, 2019Co-Authors: Michael L. Martini, Marc G. Caron, Xi Ping Huang, John D. Mccorvy, Jing Liu, Caroline A. Ray, Aarti N. Urs, Nikhil M. Urs, Bryan L. RothAbstract:G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed Functionally selective or biased ligands. A class of novel non-catechol G protein-biased agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure–Functional Selectivity relationship study measuring GS and β-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse Functional Selectivity profiles. Some compounds became potent full agonists of β-arrestin2 recruitment, while others displayed enhanced GS bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered Functional Selectivity profile demonstrated excellent blood–brain barrier penetration. This study provides novel tools for studyin...
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structure Functional Selectivity relationship studies of β arrestin biased dopamine d2 receptor agonists
Journal of Medicinal Chemistry, 2012Co-Authors: Xin Chen, Maria F. Sassano, Lianyou Zheng, Vincent Setola, Meng Chen, Xu Bai, Stephen V. Frye, William C. Wetsel, Bryan L. RothAbstract:Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: “structure–Functional Selectivity relationships” (SFSR). We recently disclosed the first β-arrestin-biased dopamine D2 receptor (D2R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D2R agonists. These studies provide a successful proof-of-concept for how Functionally selective ligands can be discovered.
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Structure–Functional Selectivity Relationship Studies of β-Arrestin-Biased Dopamine D2 Receptor Agonists
Journal of medicinal chemistry, 2012Co-Authors: Xin Chen, Bryan L. Roth, Maria F. Sassano, Lianyou Zheng, Vincent Setola, Meng Chen, Xu Bai, Stephen V. Frye, William C. Wetsel, Jian JinAbstract:Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: “structure–Functional Selectivity relationships” (SFSR). We recently disclosed the first β-arrestin-biased dopamine D2 receptor (D2R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D2R agonists. These studies provide a successful proof-of-concept for how Functionally selective ligands can be discovered.
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Genetic Deletion of p90 Ribosomal S6 Kinase 2 Alters Patterns of 5-Hydroxytryptamine2A Serotonin Receptor Functional Selectivity
Molecular pharmacology, 2009Co-Authors: Ryan T. Strachan, Noah Sciaky, Mark R. Cronan, Wesley K. Kroeze, Bryan L. RothAbstract:The concept of Functional Selectivity has now thoroughly supplanted the previously entrenched notion of intrinsic efficacy by explaining how agonists and antagonists exhibit a range of efficacies for distinct receptor-mediated responses. It is noteworthy that Functional Selectivity accommodates significant changes in efficacy resulting from differential expression of G protein-coupled receptor modifying proteins (i.e., "conditional efficacy")-a phenomenon with profound implications for drug discovery. We have uncovered a novel regulatory mechanism whereby p90 ribosomal S6 kinase 2 (RSK2) interacts with 5-hydroxytryptamine(2A) (5-HT(2A)) serotonin receptors and attenuates receptor signaling via direct receptor phosphorylation (Proc Natl Acad Sci U S A 103:4717-4722, 2006; J Biol Chem 284:5557-5573, 2009). This discovery, together with the mounting evidence for conditional efficacy, suggested to us that 5-HT(2A) agonist signaling might be disproportionately affected by alterations in RSK2 expression. To test this hypothesis, we evaluated a chemically diverse set of 5-HT(2A) agonists at three readouts of 5-HT(2A) receptor activation in both wild-type (WT) and RSK2 knock-out (KO) mouse embryonic fibroblasts (MEFs). Here we report that 5-HT(2A) receptor agonist efficacies were significantly and variably augmented in RSK2 KO MEFs compared with WT MEFs. As a result, relative agonist efficacies were significantly altered, and even reversed, between WT and RSK2 KO MEFs for a single effector readout. This study provides the first evidence that deletion of a single kinase can elicit profound changes in patterns of agonist Functional Selectivity.
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Historical Overview of the Concept of Functional Selectivity
Functional Selectivity of G Protein-Coupled Receptor Ligands, 2009Co-Authors: Bryan L. RothAbstract:A historical overview of the concept of drug action and Functional Selectivity is provided. The earliest notions of drug-receptor interactions could not account for the diversity of effects induced by ligand-binding to a receptor. Indeed it has been clear at least since 1965 that the simple notions of “intrinsic activity” cannot not account for agonist and partial agonist actions at receptors. More recent findings have unequivocally demonstrated that Functional Selectivity is a fact. In this chapter, the therapeutic implications of this conceptual revolution are emphasized.
Arthur Christopoulos - One of the best experts on this subject based on the ideXlab platform.
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a simple method for quantifying Functional Selectivity and agonist bias
ACS Chemical Neuroscience, 2012Co-Authors: Terrence Peter Kenakin, Christian Watson, Vanessa Munizmedina, Arthur Christopoulos, Steven NovickAbstract:Activation of seven-transmembrane (7TM) receptors by agonists does not always lead to uniform activation of all signaling pathways mediated by a given receptor. Relative to other ligands, many agonists are “biased” toward producing subsets of receptor behaviors. A hallmark of such “Functional Selectivity” is cell type dependence; this poses a particular problem for the profiling of agonists in whole cell test systems removed from the therapeutic one(s). Such response-specific cell-based variability makes it difficult to guide medicinal chemistry efforts aimed at identifying and optimizing therapeutically meaningful agonist bias. For this reason, we present a scale, based on the Black and Leff operational model, that contains the key elements required to describe 7TM agonism, namely, affinity (KA–1) for the receptor and efficacy (τ) in activating a particular signaling pathway. Utilizing a “transduction coefficient” term, log(τ/KA), this scale can statistically evaluate selective agonist effects in a manne...
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ligand Functional Selectivity and quantitative pharmacology at g protein coupled receptors
Expert Opinion on Drug Discovery, 2011Co-Authors: Wayne Stallaert, Arthur Christopoulos, Michael BouvierAbstract:Introduction: In recent years, it has become clear that individual GPCRs can elicit multiple G-protein-dependent and -independent cellular responses. This has led to the discovery that certain ligands can differentially modulate these responses, a concept known as Functional Selectivity. Areas covered: In this review, the authors describe the various manifestations of Functional Selectivity and its potential implication in drug discovery. The authors provide a historical perspective of the observations and methodologies that led to the evolution of this concept. The authors also describe the proposed molecular mechanisms responsible for the engagement of distinct subsets of signaling repertoire by different ligands. The review offers the reader a synthetic view of how Functional Selectivity could be used in the design of safer and more effective drugs. Expert opinion: Our better understanding of the various ways by which compounds modulate GPCR activity has led to a parallel expansion of the terminology u...
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Detection of Novel Functional Selectivity at M3 Muscarinic Acetylcholine Receptors Using a Saccharomyces cerevisiae Platform
ACS chemical biology, 2010Co-Authors: Gregory D Stewart, Patrick M Sexton, Arthur ChristopoulosAbstract:“Functional Selectivity”, although new to many chemists and biologists only a few years ago, has now become a dominant theme in drug discovery. This concept posits that different ligands engender u...
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determination of adenosine a1 receptor agonist and antagonist pharmacology using saccharomyces cerevisiae implications for ligand screening and Functional Selectivity
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Gregory D Stewart, Celine Valant, Patrick M Sexton, Peter J Scammells, Simon J Dowell, Dalibor Mijaljica, Rodney J Devenish, Arthur ChristopoulosAbstract:The budding yeast, Saccharomyces cerevisiae, is a convenient system for coupling heterologous G protein-coupled receptors (GPCRs) to the pheromone response pathway to facilitate empirical ligand screening and/or GPCR mutagenesis studies. However, few studies have applied this system to define GPCR-G protein-coupling preferences and furnish information on ligand affinities, efficacies, and Functional Selectivity. We thus used different S. cerevisiae strains, each expressing a specific human Gα/yeast Gpa1 protein chimera, and determined the pharmacology of various ligands of the coexpressed human adenosine A1 receptor. These assays, in conjunction with the application of quantitative models of agonism and antagonism, revealed that (−)-N6-(2-phenylisopropyl)adenosine was a high-efficacy agonist that selectively coupled to Gpa/1Gαo, Gpa1/Gαi1/2, and Gpa1/Gαi3, whereas the novel compound, 5′-deoxy-N6-(endo-norborn-2-yl)-5′-(2-fluorophenylthio)adenosine (VCP-189), was a lower-efficacy agonist that selectively coupled to Gpa1/Gαi proteins; the latter finding suggested that VCP-189 might be Functionally selective. The affinity of the antagonist, 8-cyclopentyl-1,3-dipropylxanthine, was also determined at the various strains. Subsequent experiments performed in mammalian Chinese hamster ovary cells monitoring cAMP formation/inhibition, intracellular calcium mobilization, phosphorylation of extracellular signal-regulated kinase 1 and 2 or 35S-labeled guanosine 5′-(γ-thio)triphosphate binding, were in general agreement with the yeast data regarding agonist efficacy estimation and antagonist affinity estimation, but revealed that the apparent Functional Selectivity of VCP-189 could be explained by differences in stimulus-response coupling between yeast and mammalian cells. Our results suggest that this yeast system is a useful tool for quantifying ligand affinity and relative efficacy, but it may lack the sensitivity required to detect Functional Selectivity of low-efficacy agonists.
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a novel mechanism of g protein coupled receptor Functional Selectivity muscarinic partial agonist mcn a 343 as a bitopic orthosteric allosteric ligand
Journal of Biological Chemistry, 2008Co-Authors: Celine Valant, Patrick M Sexton, Peter J Scammells, Karen J Gregory, Nathan E Hall, Michael J Lew, Arthur ChristopoulosAbstract:Many G protein-coupled receptors (GPCRs) possess allosteric binding sites distinct from the orthosteric site utilized by their cognate ligands, but most GPCR allosteric modulators reported to date lack signaling efficacy in their own right. McN-A-343 (4-(N-(3-chlorophenyl)carbamoyloxy)-2-butynyltrimethylammonium chloride) is a Functionally selective muscarinic acetylcholine receptor (mAChR) partial agonist that can also interact allosterically at the M2 mAChR. We hypothesized that this molecule simultaneously utilizes both an allosteric and the orthosteric site on the M2 mAChR to mediate these effects. By synthesizing progressively truncated McN-A-343 derivatives, we identified two, which minimally contain 3-chlorophenylcarbamate, as pure allosteric modulators. These compounds were positive modulators of the orthosteric antagonist N-[3H]methylscopolamine, but in Functional assays of M2 mAChR-mediated ERK1/2 phosphorylation and guanosine 5′-3-O-([35S]thio)triphosphate binding, they were negative modulators of agonist efficacy. This negative allosteric effect was diminished upon mutation of Y177A in the second extracellular (E2) loop of the M2 mAChR that is known to reduce prototypical allosteric modulator potency. Our results are consistent with McN-A-343 being a bitopic orthosteric/allosteric ligand with the allosteric moiety engendering partial agonism and Functional Selectivity. This finding suggests a novel and largely unappreciated mechanism of “directed efficacy” whereby Functional Selectivity may be engendered in a GPCR by utilizing an allosteric ligand to direct the signaling of an orthosteric ligand encoded within the same molecule.
Gunnar Schulte - One of the best experts on this subject based on the ideXlab platform.
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systematic mapping of wnt fzd protein interactions reveals Functional Selectivity by distinct wnt fzd pairs
Journal of Biological Chemistry, 2015Co-Authors: Jacomijn P Dijksterhuis, Bolormaa Baljinnyam, Karen Stanger, Hakki Ogun Sercan, Osler Andres, Jeffrey S Rubin, Rami N Hannoush, Gunnar SchulteAbstract:The seven-transmembrane-spanning receptors of the FZD1–10 class are bound and activated by the WNT family of lipoglycoproteins, thereby inducing a complex network of signaling pathways. However, the specificity of the interaction between mammalian WNT and FZD proteins and the subsequent signaling cascade downstream of the different WNT-FZD pairs have not been systematically addressed to date. In this study, we determined the binding affinities of various WNTs for different members of the FZD family by using bio-layer interferometry and characterized their Functional Selectivity in a cell system. Using purified WNTs, we show that different FZD cysteine-rich domains prefer to bind to distinct WNTs with fast on-rates and slow off-rates. In a 32D cell-based system engineered to overexpress FZD2, FZD4, or FZD5, we found that WNT-3A (but not WNT-4, -5A, or -9B) activated the WNT-β-catenin pathway through FZD2/4/5 as measured by phosphorylation of LRP6 and β-catenin stabilization. Surprisingly, different WNT-FZD pairs showed differential effects on phosphorylation of DVL2 and DVL3, revealing a previously unappreciated DVL isoform Selectivity by different WNT-FZD pairs in 32D cells. In summary, we present extensive mapping of WNT-FZD cysteine-rich domain interactions complemented by analysis of WNT-FZD pair Functionality in a unique cell system expressing individual FZD isoforms. Differential WNT-FZD binding and selective Functional readouts suggest that endogenous WNT ligands evolved with an intrinsic natural bias toward different downstream signaling pathways, a phenomenon that could be of great importance in the design of FZD-targeting drugs.
Nikhil M. Urs - One of the best experts on this subject based on the ideXlab platform.
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Structure-Functional-Selectivity Relationship Studies of Novel Apomorphine Analogs to Develop D1R/D2R Biased Ligands
ACS medicinal chemistry letters, 2020Co-Authors: Hyejin Park, Aarti N. Urs, Joseph Zimmerman, Chuan Liu, Qiu Wang, Nikhil M. UrsAbstract:Loss of dopamine neurons is central to the manifestation of Parkinson's disease motor symptoms. The dopamine precursor L-DOPA, the most commonly used therapeutic agent for Parkinson's disease, can restore normal movement yet cause side-effects such as dyskinesias upon prolonged administration. Dopamine D1 and D2 receptors activate G-protein- and arrestin-dependent signaling pathways that regulate various dopamine-dependent functions including locomotion. Studies have shown that shifting the balance of dopamine receptor signaling toward the arrestin pathway can be beneficial for inducing normal movement, while reducing dyskinesias. However, simultaneous activation of both D1 and D2Rs is required for robust locomotor activity. Thus, it is desirable to develop ligands targeting both D1 and D2Rs and their Functional Selectivity. Here, we report structure-Functional-Selectivity relationship (SFSR) studies of novel apomorphine analogs to identify structural motifs responsible for biased activity at both D1 and D2Rs.
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Defining Structure-Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists.
Journal of medicinal chemistry, 2019Co-Authors: Michael L. Martini, Marc G. Caron, Xi Ping Huang, John D. Mccorvy, Jing Liu, Caroline A. Ray, Aarti N. Urs, Nikhil M. Urs, Bryan L. RothAbstract:G protein-coupled receptors (GPCRs) are capable of downstream signaling through distinct noncanonical pathways such as β-arrestins in addition to the canonical G protein-dependent pathways. GPCR ligands that differentially activate the downstream signaling pathways are termed Functionally selective or biased ligands. A class of novel non-catechol G protein-biased agonists of the dopamine D1 receptor (D1R) was recently disclosed. We conducted the first comprehensive structure–Functional Selectivity relationship study measuring GS and β-arrestin2 recruitment activities focused on four regions of this scaffold, resulting in over 50 analogs with diverse Functional Selectivity profiles. Some compounds became potent full agonists of β-arrestin2 recruitment, while others displayed enhanced GS bias compared to the starting compound. Pharmacokinetic testing of an analog with an altered Functional Selectivity profile demonstrated excellent blood–brain barrier penetration. This study provides novel tools for studyin...
Terry P Kenakin - One of the best experts on this subject based on the ideXlab platform.
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the role of conformational ensembles of seven transmembrane receptors in Functional Selectivity
Current Opinion in Pharmacology, 2010Co-Authors: Nagarajan Vaidehi, Terry P KenakinAbstract:It has been observed that some ligands cause receptors to selectively interact with subsets of signaling proteins to 'bias' their signaling; this is inconsistent with receptors forming a single active state. Here we review the concept of receptor conformation ensembles that can account for a given agonist showing varied efficacies for different signaling pathways. Data show that agonists can stabilize different receptor conformations. We provide a demonstration at the molecular level of how the various receptor conformations in the ensemble can produce Functional Selectivity for signaling pathways. Specifically, agonists that selectively stabilize certain receptor conformations from the ensemble can produce biased agonism towards this signaling pathway. These ideas are described with data supported from recent computations of the potential energy surface of the β2-adrenergic receptor.
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Functional Selectivity and Biased Receptor Signaling
The Journal of pharmacology and experimental therapeutics, 2010Co-Authors: Terry P KenakinAbstract:With the emergence of information describing Functional Selectivity and biased agonists and antagonists has come a lack of confidence in “one size fits all” assays for detection of agonism. Seven-transmembrane receptors are pleiotropic with respect to the signaling protein to which they couple in a cell, and many conformations of the receptor can be formed; this leads to systems where ligands can stabilize unique conformations that go on to selectively activate signaling pathways. Thus, such “biased” ligands can produce cell-specific agonism that may require targeted assays to detect and quantify. It also predicts that ligands can have many different efficacies for the many behaviors that the receptor can exhibit (referred to as “pluridimensional efficacy”), leading to a breakdown in the common classifications of agonist and antagonist. This all poses unique challenges to the pharmacologic nomenclature of drugs, the detection and optimization of new drugs, and the association of phenotypic clinical profiles with pharmacological properties of drugs.
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seven transmembrane receptors as shapeshifting proteins the impact of allosteric modulation and Functional Selectivity on new drug discovery
Pharmacological Reviews, 2010Co-Authors: Terry P Kenakin, Laurence J MillerAbstract:It is useful to consider seven transmembrane receptors (7TMRs) as disordered proteins able to allosterically respond to a number of binding partners. Considering 7TMRs as allosteric systems, affinity and efficacy can be thought of in terms of energy flow between a modulator, conduit (the receptor protein), and a number of guests. These guests can be other molecules, receptors, membrane-bound proteins, or signaling proteins in the cytosol. These vectorial flows of energy can yield standard canonical guest allostery (allosteric modification of drug effect), effects along the plane of the cell membrane (receptor oligomerization), or effects directed into the cytosol (differential signaling as Functional Selectivity). This review discusses these apparently diverse pharmacological effects in terms of molecular dynamics and protein ensemble theory, which tends to unify 7TMR behavior toward cells. Special consideration will be given to Functional Selectivity (biased agonism and biased antagonism) in terms of mechanism of action and potential therapeutic application. The explosion of technology that has enabled observation of diverse 7TMR behavior has also shown how drugs can have multiple (pluridimensional) efficacies and how this can cause paradoxical drug classification and nomenclatures.
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Functional Selectivity: Theoretical Considerations and Future Directions
Functional Selectivity of G Protein-Coupled Receptor Ligands, 2009Co-Authors: Terry P KenakinAbstract:The selective activation of receptors by some agonists to emphasize some but not all aspects of the receptor signaling capability was proposed on theoretical grounds in 1995 because of data showing reversal of relative orders of potency for different stimulus pathways linked to a single receptor. These data precluded the notion that all agonists produce a single receptor active state. Since that time, a number of different lines of evidence indicate that ligands can bias receptor toward different pathways in cells. Conformational selection within the ensemble of conformation receptors formed during normal function theoretically is capable of producing Functional Selectivity; this chapter discusses the thermodynamic nature of this effect. Finally, although Functional Selectivity is a well-documented pharmacological phenomenom duplicated in many laboratories, it is still unclear whether it can be harnessed to produce therapeutically unique effect; it is hoped that studies in translational medicine with Functionally selective ligands will furnish the link to therapy.
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Functional Selectivity through protean and biased agonism: who steers the ship?
Molecular pharmacology, 2007Co-Authors: Terry P KenakinAbstract:This article describes Functional Selectivity of agonists and antagonists and distinguishes conventional cell-based Functional Selectivity, where the strength of signal produces selective signaling in various organs, from true receptor active-state based Selectivity, also alternatively referred to in the literature as “stimulus trafficking,” “biased agonism,” and “collateral efficacy.” This latter mechanism of Selectivity depends on the ligand-related conformation of the receptor and is not compatible with the parsimonious view that agonists produce a single receptor active state. In addition, protean agonism is described, whereby a ligand produces positive agonism in quiescent systems and inverse agonism in constitutively active systems. This is a special case of active state-based Selectivity in which the ligand produces an active state that is of lower efficacy than the natural constitutively active state. It is postulated that receptor active-state based Selectivity, unlike cell-based Functional Selectivity, is controllable through the chemical structure of the ligand and is therefore more likely to be a viable avenue for therapeutic Selectivity in the clinic. Reasons are given for differentiating receptor active-state based Selectivity from conventional Functional organ Selectivity.
