Research Repository

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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), doi: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

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), doi:10.1124/mol.117.110890. ISSN 0026-895X

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

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, doi:10.1038/s41598-018-21100-x. ISSN 2045-2322

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

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), doi: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

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, doi:10.1021/acsmedchemlett.7b00157. ISSN 1948-5875

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

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), doi: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

Long receptor residence time of C26 contributes to super agonist activity at the human β2 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), doi:10.1124/mol.115.101253. ISSN 0026-895X

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