All Outputs (52)

NanoBiT Complementation to Monitor Agonist-Induced Adenosine A1 Receptor Internalization (2019)
Journal Article
Soave, M., Kellam, B., Woolard, J., Briddon, S. J., & Hill, S. J. (2019). NanoBiT Complementation to Monitor Agonist-Induced Adenosine A1 Receptor Internalization. Slas Discovery, https://doi.org/10.1177/2472555219880475

Receptor internalization in response to prolonged agonist treatment is an important regulator of G protein–coupled receptor (GPCR) function. The adenosine A1 receptor (A1AR) is one of the adenosine receptor family of GPCRs, and evidence for its agoni... Read More about NanoBiT Complementation to Monitor Agonist-Induced Adenosine A1 Receptor Internalization.

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.

Modulators of CXCR4 and CXCR7/ACKR3 Function (2019)
Journal Article
Adlere, I., Caspar, B., Arimont, M., Dekkers, S., Visser, K., Stuijt, J., …Leurs, R. (2019). Modulators of CXCR4 and CXCR7/ACKR3 Function. Molecular Pharmacology, 96(6), 737-752. https://doi.org/10.1124/mol.119.117663

Copyright © 2019 by The Author(s). The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for hu... Read More about Modulators of CXCR4 and CXCR7/ACKR3 Function.

Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor (2019)
Journal Article
Fyfe, T. J., Kellam, B., Mistry, S. N., Scammells, P. J., Lane, J. R., & Capuano, B. (2019). Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor. European Journal of Medicinal Chemistry, 168, 474-490. https://doi.org/10.1016/j.ejmech.2019.01.061

We recently described a structurally novel series of negative allosteric modulators (NAMs) of the dopamine D2 receptor (D2R) based on thieno[2,3-d]pyrimidine 1, showing it can be structurally simplified to reveal low molecular weight, fragment-like N... Read More about Subtle modifications to a thieno[2,3-d]pyrimidine scaffold yield negative allosteric modulators and agonists of the dopamine D2 receptor.

Visualising ligand-binding to a GPCR in vivo using nanoBRET (2018)
Journal Article
Carvalheira Alcobia, D., Ziegler, A. I., Kondrashov, A., Comeo, E., Mistry, S., Kellam, B., …Sloan, E. K. (2018). Visualising ligand-binding to a GPCR in vivo using nanoBRET. iScience, 6(8), 280-288. https://doi.org/10.1016/j.isci.2018.08.006

© 2018 The Author(s) The therapeutic action of a drug depends on its ability to engage with its molecular target in vivo. However, current drug discovery strategies quantify drug levels within organs rather than determining the binding of drugs direc... Read More about Visualising ligand-binding to a GPCR in vivo using nanoBRET.

Nucleoside based self-assembling drugs for localized drug delivery (2018)
Journal Article
Skilling, K. J., Stocks, M. J., Kellam, B., Ashford, M., Bradshaw, T., Burroughs, L., & Marlow, M. (in press). Nucleoside based self-assembling drugs for localized drug delivery. ChemMedChem, https://doi.org/10.1002/cmdc.201800063

We have synthesized a range of gelators based on nucleoside analogues gemcitabine and lamivudine, characterizing representative gels from the series using rheology and TEM. Growth inhibition studies of gemcitabine derivatives confirmed the feasibilit... Read More about Nucleoside based self-assembling drugs for localized drug delivery.

A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor (2018)
Journal Article
Fyfe, T. J., Zarzycka, B., Lim, H. D., Kellam, B., Mistry, S. N., Katrich, V., …Capuano, B. (2019). A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor. Journal of Medicinal Chemistry, 62(1), 174–206. https://doi.org/10.1021/acs.jmedchem.7b01565

Recently, a novel negative allosteric modulator (NAM) of the D 2-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3-d]pyrimidine scaffold that does not feature in known dopaminergic ligands.... Read More about A thieno[2,3-d]pyrimidine scaffold is a novel negative allosteric modulator of the dopamine D2 receptor.

Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925 (2018)
Journal Article
Conroy, S., Kindon, N., Glenn, J., Stoddart, L. A., Lewis, R. J., Hill, S. J., …Stocks, M. J. (2018). Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925. Journal of Medicinal Chemistry, 61(7), https://doi.org/10.1021/acs.jmedchem.8b00139

The human P2Y2 receptor (hP2Y2R) is a G protein-coupled receptor that shows promise as a therapeutic target for many important conditions including anti-metastatic cancer therapy and more recently for the treatment of idiopathic pulmonary fibrosis. A... Read More about Synthesis and evaluation of the first fluorescent antagonists of the human P2Y2 receptor based on AR-C118925.

Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation (2018)
Journal Article
Citossi, F., Smith, T., Lee, J. B., Segal, J., Gershkovich, P., Stocks, M. J., …Marlow, M. (in press). Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation. Molecular Pharmaceutics, 15(4), https://doi.org/10.1021/acs.molpharmaceut.7b01106

Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing poly-mer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assemb... Read More about Self-assembling benzothiazole-based gelators: a mechanistic understanding of in vitro bioactivation and gelation.

Development of novel fluorescent histamine H?-receptor antagonists to study ligand-binding kinetics in living cells (2018)
Journal Article
Stoddart, L. A., Vernall, A. J., Bouzo-Lorenzo, M., Bosma, R., Kooistra, A. J., de Graaf, C., …Hill, S. J. (2018). Development of novel fluorescent histamine H₁-receptor antagonists to study ligand-binding kinetics in living cells. Scientific Reports, 8, Article 1572. https://doi.org/10.1038/s41598-018-19714-2

The histamine H1-receptor (H1R) is an important mediator of allergy and inflammation. H1R antagonists have particular clinical utility in allergic rhinitis and urticaria. Here we have developed six novel fluorescent probes for this receptor that are... Read More about Development of novel fluorescent histamine H?-receptor antagonists to study ligand-binding kinetics in living cells.

Fluorescently Labeled Morphine Derivatives for Bioimaging Studies (2018)
Journal Article
Lam, R., Gondin, A. B., Canals, M., Kellam, B., Briddon, S. J., Graham, B., & Scammells, P. J. (2018). Fluorescently Labeled Morphine Derivatives for Bioimaging Studies. Journal of Medicinal Chemistry, 61(3), 1316-1329. https://doi.org/10.1021/acs.jmedchem.7b01811

Opioids, like morphine, are the mainstay analgesics for the treatment and control of pain. Despite this, they often exhibit severe side effects that limit dose; patients often become tolerant and dependent on these drugs, which remains a major health... Read More about Fluorescently Labeled Morphine Derivatives for Bioimaging Studies.

A non-imaging high throughput approach to chemical library screening at the unmodified adenosine-A3 receptor in living cells (2017)
Journal Article
Arruda, M. A., Stoddart, L. A., Gherbi, K., Briddon, S. J., Kellam, B., & Hill, S. J. (in press). A non-imaging high throughput approach to chemical library screening at the unmodified adenosine-A3 receptor in living cells. Frontiers in Pharmacology, 8(908), https://doi.org/10.3389/fphar.2017.00908

Recent advances in fluorescent ligand technology have enabled the study of G protein-coupled receptors in their native environment without the need for genetic modification such as addition of N-terminal fluorescent or bioluminescent tags. Here, we h... Read More about A non-imaging high throughput approach to chemical library screening at the unmodified adenosine-A3 receptor in living cells.

Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease (2017)
Journal Article
Baker, J. G., Gardiner, S. M., Woolard, J., Fromont, C., Jadhav, G. P., Mistry, S. N., …Fischer, P. M. (2017). Novel selective β1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease. FASEB Journal, 31(7), 3150-3166. https://doi.org/10.1096/fj.201601305R

?-Blockers reduce mortality and improve symptoms in people with heart disease. However, current clinically available ?-blockers have poor selectivity for the cardiac ?1-adrenoceptor (AR) over the lung ?2-AR. Unwanted ?2-blockade risks causing life-th... Read More about Novel selective ?1-adrenoceptor antagonists for concomitant cardiovascular and respiratory disease.

Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors (2017)
Journal Article
Schwehm, C., Kellam, B., Garces, A., Hill, S. J., Kindon, N., Bradshaw, T. D., …Stocks, M. (2017). Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors. Journal of Medicinal Chemistry, 60(4), https://doi.org/10.1021/acs.jmedchem.6b01801

A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize p... Read More about Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors.

Developing a self-healing supramolecular nucleoside hydrogel (2016)
Journal Article
Skilling, K. J., Kellam, B., Ashford, M., Bradshaw, T. D., & Marlow, M. (2016). Developing a self-healing supramolecular nucleoside hydrogel. Soft Matter, 12(43), 8950-8957. https://doi.org/10.1039/c6sm01779g

© 2016 The Royal Society of Chemistry. Low molecular weight gelator hydrogels provide a viable alternative to traditional polymer based drug delivery platforms, owing to their tunable stability and in most cases inherent biocompatibility. Here we rep... Read More about Developing a self-healing supramolecular nucleoside hydrogel.

GPCRs through the keyhole: the role of protein flexibility in ligand binding to ?-adrenoceptors (2016)
Journal Article
Emtage, A. L., Mistry, S. N., Fischer, P. M., Kellam, B., & Laughton, C. A. (2017). GPCRs through the keyhole: the role of protein flexibility in ligand binding to ?-adrenoceptors. Journal of Biomolecular Structure and Dynamics, 35(12), 2604-2619. https://doi.org/10.1080/07391102.2016.1226197

© 2016 Informa UK Limited, trading as Taylor & Francis Group. G protein-coupled receptors (GPCRs) are proteins of pharmaceutical importance, with over 30% of all drugs in clinical use targeting them. Increasing numbers of X-ray crystal (XRC) struct... Read More about GPCRs through the keyhole: the role of protein flexibility in ligand binding to ?-adrenoceptors.

Drug-like antagonists of P2Y receptors — from lead identification to drug development (2016)
Journal Article
Conroy, S., Kindon, N., Kellam, B., & Stocks, M. (in press). Drug-like antagonists of P2Y receptors — from lead identification to drug development. Journal of Medicinal Chemistry, https://doi.org/10.1021/acs.jmedchem.5b01972

P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G p... Read More about Drug-like antagonists of P2Y receptors — from lead identification to drug development.

Alkylation of staurosporine to derive a kinase probe for fluorescence applications (2016)
Journal Article
Disney, A. J., Kellam, B., & Dekker, L. V. (in press). Alkylation of staurosporine to derive a kinase probe for fluorescence applications. ChemMedChem, 11, https://doi.org/10.1002/cmdc.201500589

The natural product staurosporine is a high-affinity inhibitor of nearly all mammalian protein kinases.The labelling of staurosporine has proven effective as a means of generating protein kinase research tools. Most tools have been generated by acyla... Read More about Alkylation of staurosporine to derive a kinase probe for fluorescence applications.

Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the ?-Opioid Receptor (2015)
Journal Article
Schembri, L. S., Stoddart, L. A., Briddon, S. J., Kellam, B., Canals, M., Graham, B., & Scammells, P. J. (2015). Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the ?-Opioid Receptor. Journal of Medicinal Chemistry, 58(24), 9754-9767. https://doi.org/10.1021/acs.jmedchem.5b01664

Fluorescently labeled ligands are useful pharmacological research tools for studying receptor localization, trafficking, and signaling processes via fluorescence imaging. They are also employed in fluorescent binding assays. This study is centered on... Read More about Synthesis, Biological Evaluation, and Utility of Fluorescent Ligands Targeting the ?-Opioid Receptor.

Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery (2015)
Journal Article
Stone, E. L., Citossi, F., Singh, R., Kaur, B., Gaskell, M., Farmer, P. B., …Bradshaw, T. D. (2015). Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery. Bioorganic and Medicinal Chemistry, 23(21), 6891-6899. https://doi.org/10.1016/j.bmc.2015.09.052

Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts’ generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles’ activity. Treatment of sensit... Read More about Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery.