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Development of novel fluorescent histamine H?-receptor antagonists to study ligand-binding kinetics in living cells

Stoddart, Leigh A.; Vernall, Andrea J.; Bouzo-Lorenzo, Monica; Bosma, Reggie; Kooistra, Albert J.; de Graaf, Chris; Vischer, Henry F.; Leurs, Rob; Briddon, Stephen J.; Kellam, Barrie; Hill, Stephen J.


Leigh A. Stoddart

Andrea J. Vernall

Monica Bouzo-Lorenzo

Reggie Bosma

Albert J. Kooistra

Chris de Graaf

Henry F. Vischer

Rob Leurs

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Professor of Medicinal Chemistry

Professor of Molecular Pharmacology


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 very effective for high resolution confocal imaging, alongside bioluminescence resonance energy transfer approaches to monitor H1R ligand binding kinetics in living cells. The latter technology exploits the opportunities provided by the recently described bright bioluminescent protein NanoLuc when it is fused to the N-terminus of a receptor. Two different pharmacophores (mepyramine or the fragment VUF13816) were used to generate fluorescent H1R antagonists conjugated via peptide linkers to the fluorophore BODIPY630/650. Kinetic properties of the probes showed wide variation, with the VUF13816 analogues having much longer H1R residence times relative to their mepyramine-based counterparts. The kinetics of these fluorescent ligands could also be monitored in membrane preparations providing new opportunities for future drug discovery applications.


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.

Journal Article Type Article
Acceptance Date Jan 3, 2018
Online Publication Date Jan 25, 2018
Publication Date Dec 1, 2018
Deposit Date Jan 19, 2018
Publicly Available Date Jan 25, 2018
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 8
Article Number 1572
Public URL
Publisher URL
Additional Information Received: 25 October 2017; Accepted: 3 January 2018; First Online: 25 January 2018; : The authors declare that they have no competing interests.


s41598-018-19714-2.pdf (5.2 Mb)

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