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Design, Synthesis, and Application of Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the CXC Chemokine Receptor 2 (2023)
Journal Article
Casella, B. M., Farmer, J. P., Nesheva, D. N., Williams, H. E., Charlton, S. J., Holliday, N. D., …Mistry, S. N. (2023). Design, Synthesis, and Application of Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the CXC Chemokine Receptor 2. Journal of Medicinal Chemistry, https://doi.org/10.1021/acs.jmedchem.3c00849

The inhibition of CXC chemokine receptor 2 (CXCR2), a key inflammatory mediator, is a potential strategy in the treatment of several pulmonary diseases and cancers. The complexity of endogenous chemokine interaction with the orthosteric binding site... Read More about Design, Synthesis, and Application of Fluorescent Ligands Targeting the Intracellular Allosteric Binding Site of the CXC Chemokine Receptor 2.

Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor (2019)
Journal Article
Fyfe, T. J., Kellam, B., Sykes, D. A., Capuano, B., Scammells, P. J., Lane, J. R., …Mistry, S. N. (2019). Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor. Journal of Medicinal Chemistry, 62(21), 9488-9520. https://doi.org/10.1021/acs.jmedchem.9b00864

Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side-effects (EPS) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with c... Read More about Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor.

Investigating the Influence of Tracer Kinetics on Competition-Kinetic Association Binding Assays: Identifying the Optimal Conditions for Assessing the Kinetics of Low-Affinity Compounds (2019)
Journal Article
Sykes, D. A., Jain, P., & Charlton, S. J. (2019). Investigating the Influence of Tracer Kinetics on Competition-Kinetic Association Binding Assays: Identifying the Optimal Conditions for Assessing the Kinetics of Low-Affinity Compounds. Molecular Pharmacology, 96(3), 378-392. https://doi.org/10.1124/mol.119.116764

An increased appreciation of the importance of optimizing drug-binding kinetics has lead to the development of various techniques for measuring the kinetics of unlabeled compounds. One approach is the competition-association kinetic binding method fi... Read More about Investigating the Influence of Tracer Kinetics on Competition-Kinetic Association Binding Assays: Identifying the Optimal Conditions for Assessing the Kinetics of Low-Affinity Compounds.

Pharmacological characterization of a novel 5-hydroxybenzothiazolone-derived b2-adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies (2019)
Journal Article
Koziczak-Holbro, M., Rigel, D. F., Dumotier, B., Sykes, D. A., Tsao, J., Nguyen, N. H., …Hatakeyama, S. (2019). Pharmacological characterization of a novel 5-hydroxybenzothiazolone-derived b2-adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies. Journal of Pharmacology and Experimental Therapeutics, 369(2), 188-199. https://doi.org/10.1124/jpet.118.255307

Copyright ª 2019 by The Author(s) The anabolic effects of b2-adrenoceptor (b2-AR) agonists on skeletal muscle have been demonstrated in various species. However, the clinical use of b2-AR agonists for skeletal muscle wasting conditions has been limit... Read More about Pharmacological characterization of a novel 5-hydroxybenzothiazolone-derived b2-adrenoceptor agonist with functional selectivity for anabolic effects on skeletal muscle resulting in a wider cardiovascular safety window in preclinical studies.

Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations (2018)
Journal Article
Civciristov, S., Ellisdon, A. M., Suderman, R., Pon, C. K., Evans, B. A., Kleifeld, O., …Halls, M. L. (2018). Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations. Science Signaling, 11(551), Article eaan1188. https://doi.org/10.1126/scisignal.aan1188

G protein–coupled receptors (GPCRs) are the largest class of cell surface signaling proteins, participate in nearly all physiological processes, and are the targets of 30% of marketed drugs. Typically, nanomolar to micromolar concentrations of ligand... Read More about Preassembled GPCR signaling complexes mediate distinct cellular responses to ultralow ligand concentrations.

The inhibition of human lung fibroblast proliferation and differentiation by Gs-coupled receptors is not predicted by the magnitude of cAMP response (2018)
Journal Article
Roberts, M. J., Broome, R. E., Kent, T. C., Charlton, S. J., & Rosethorne, E. M. (2018). The inhibition of human lung fibroblast proliferation and differentiation by Gs-coupled receptors is not predicted by the magnitude of cAMP response. Respiratory Research, 19, Article 56. https://doi.org/10.1186/s12931-018-0759-2

Background Idiopathic pulmonary fibrosis (IPF) is 22 a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel t... Read More about The inhibition of human lung fibroblast proliferation and differentiation by Gs-coupled receptors is not predicted by the magnitude of cAMP response.

Biased agonism in drug discovery: is it too soon to choose a path? (2018)
Journal Article
Michel, M. C., & Charlton, S. J. (2018). Biased agonism in drug discovery: is it too soon to choose a path?. Molecular Pharmacology, 93(4), https://doi.org/10.1124/mol.117.110890

A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists stabilize receptor conformations preferentially stimulating one of these pathways, and therefore allow a more tar... Read More about Biased agonism in drug discovery: is it too soon to choose a path?.

Micro-pharmacokinetics: quantifying local drug concentration at live cell membranes (2018)
Journal Article
Gherbi, K., Briddon, S. J., & Charlton, S. J. (in press). Micro-pharmacokinetics: quantifying local drug concentration at live cell membranes. Scientific Reports, 8, Article 3479. https://doi.org/10.1038/s41598-018-21100-x

Fundamental equations for determining pharmacological parameters, such as the binding afnity of a ligand for its target receptor, assume a homogeneous distribution of ligand, with concentrations in the immediate vicinity of the receptor being the sam... Read More about Micro-pharmacokinetics: quantifying local drug concentration at live cell membranes.

Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors (2017)
Journal Article
Sykes, D. A., Moore, H., Stott, L., Holliday, N., Javitch, J. A., Lane, J. R., & Charlton, S. J. (2017). Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nature Communications, 8(1), Article 763. https://doi.org/10.1038/s41467-017-00716-z

Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. However, support for this hypothesis is limited to a relatively small number o... Read More about Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors.

Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2 receptor antagonist for treatment of asthma (2017)
Journal Article
Sandham, D. A., Barker, L., Brown, L., Brown, Z., Budd, D., Charlton, S. J., …Willis, J. (2017). Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2 receptor antagonist for treatment of asthma. ACS Medicinal Chemistry Letters, 8(5), 582-586. https://doi.org/10.1021/acsmedchemlett.7b00157

Further optimization of an initial DP2 receptor antagonist clinical candidate NVPQAV680 led to the discovery of a follow-up molecule 2-(2-methyl-1-(4-(methylsulfonyl)-2- (trifluoromethyl)benzyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetic acid (compound 11,... Read More about Discovery of fevipiprant (NVP-QAW039), a potent and selective DP2 receptor antagonist for treatment of asthma.

Uncoupling the Structure–Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding (2016)
Journal Article
Dickson, C. J., Hornak, V., Velez-Vega, C., McKay, D. J., Reilly, J., Sandham, D. A., …Duca, J. S. (2016). Uncoupling the Structure–Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding. Journal of Medicinal Chemistry, 59(12), 5780-5789. https://doi.org/10.1021/acs.jmedchem.6b00358

Ligand binding to membrane proteins may be significantly influenced by the interaction of ligands with the membrane. In particular, the microscopic ligand concentration within the membrane surface solvation layer may exceed that in bulk solvent, resu... Read More about Uncoupling the Structure–Activity Relationships of β2 Adrenergic Receptor Ligands from Membrane Binding.

Fevipiprant (QAW039), a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy (2016)
Journal Article
Sykes, D. A., Bradley, M. E., Riddy, D. M., Willard, E., Reilly, J., Miah, A., …Charlton, S. J. (2016). Fevipiprant (QAW039), a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy. Molecular Pharmacology, 89(5), 593-605. https://doi.org/10.1124/mol.115.101832

Here we describe the pharmacologic properties of a series of clinically relevant chemoattractant receptor-homologous molecules expressed on T-helper type 2 (CRTh2) receptor antagonists, including fevipiprant (NVP-QAW039 or QAW039), which is currently... Read More about Fevipiprant (QAW039), a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy.

Long receptor residence time of C26 contributes to super agonist activity at the human ?2 adrenoceptor (2016)
Journal Article
Rosethorne, E. M., Bradley, M. E., Gherbi, K., Sykes, D. A., Sattikar, A., Wright, J. D., …Charlton, S. J. (2016). Long receptor residence time of C26 contributes to super agonist activity at the human β2 adrenoceptor. Molecular Pharmacology, 89(4), 467-475. https://doi.org/10.1124/mol.115.101253

Super agonists produce greater functional responses than endogenous agonists in the same assay, and their unique pharmacology is the subject of increasing interest and debate. We propose that receptor residence time and the duration of receptor signa... Read More about Long receptor residence time of C26 contributes to super agonist activity at the human ?2 adrenoceptor.

The role of kinetic context in apparent biased agonism at GPCRs (2016)
Journal Article
Javitch, J. A., Klein Herenbrink, C., Sykes, D. A., Donthamsetti, P., Canals, M., Coudrat, T., …Lane, J. R. (2016). The role of kinetic context in apparent biased agonism at GPCRs. Nature Communications, 7, Article 10842. https://doi.org/10.1038/ncomms10842

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usu... Read More about The role of kinetic context in apparent biased agonism at GPCRs.

Simulating the influence of plasma protein on measured receptor affinity in biochemical assays reveals the utility of Schild analysis for estimating compound affinity for plasma proteins (2015)
Journal Article
Charlton, S. J., Blakeley, D., Sykes, D. A., Ensor, P., Bertran, E., Aston, P. J., & Charlton, S. J. (2015). Simulating the influence of plasma protein on measured receptor affinity in biochemical assays reveals the utility of Schild analysis for estimating compound affinity for plasma proteins. British Journal of Pharmacology, 172(21), 5037-5049. https://doi.org/10.1111/bph.13263

© 2015 The British Pharmacological Society. Background and Purpose Plasma protein binding (PPB) influences the free fraction of drug available to bind to its target and is therefore an important consideration in drug discovery. While traditional meth... Read More about Simulating the influence of plasma protein on measured receptor affinity in biochemical assays reveals the utility of Schild analysis for estimating compound affinity for plasma proteins.

Functional desensitization of the ? 2 adrenoceptor is not dependent on agonist efficacy (2015)
Journal Article
Rosethorne, E. M., Bradley, M. E., Kent, T. C., & Charlton, S. J. (2015). Functional desensitization of the ? 2 adrenoceptor is not dependent on agonist efficacy. Pharmacology Research and Perspectives, 3(1), https://doi.org/10.1002/prp2.101

© 2015 John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstru... Read More about Functional desensitization of the ? 2 adrenoceptor is not dependent on agonist efficacy.

'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models (2014)
Journal Article
Vauquelin, G., Hall, D., & Charlton, S. (2015). 'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models. British Journal of Pharmacology, 172(9), 2300-2315. https://doi.org/10.1111/bph.13053

© 2014 The British Pharmacological Society. Background and Purpose Non-competitive drugs that confer allosteric modulation of orthosteric ligand binding are of increasing interest as therapeutic agents. Sought-after advantages include a ceiling level... Read More about 'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models.

Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action (2014)
Journal Article
Bradley, M. E., Dombrecht, B., Manini, J., Willis, J., Vlerick, D., De Taeye, S., …Cromie, K. D. (2015). Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action. Molecular Pharmacology, 87(2), 251-262. https://doi.org/10.1124/mol.114.094821

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics. Chemokines and chemokine receptors are key modulators in inflammatory diseases and malignancies. Here, we describe the identification and pharmacologic character... Read More about Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action.

Observed drug-receptor association rates are governed by membrane affinity: The importance of establishing "micro-pharmacokinetic/pharmacodynamic relationships" at the ?2-adrenoceptor (2014)
Journal Article
Sykes, D. A., Parry, C., Reilly, J., Wright, P., Fairhurst, R. A., & Charlton, S. J. (2014). Observed drug-receptor association rates are governed by membrane affinity: The importance of establishing "micro-pharmacokinetic/pharmacodynamic relationships" at the ?2-adrenoceptor. Molecular Pharmacology, 85(4), 608-617. https://doi.org/10.1124/mol.113.090209

Current pharmacological models for determining affinity and kinetics of drugs for membrane receptors assume the interacting molecules are homogeneously distributed in the bulk aqueous phase. The phospholipid membrane can, however, provide a second co... Read More about Observed drug-receptor association rates are governed by membrane affinity: The importance of establishing "micro-pharmacokinetic/pharmacodynamic relationships" at the ?2-adrenoceptor.