Route to prolonged residence time at the histamine H1 receptor: Growing from desloratadine to rupatadine

Reggie Bosma, Zhiyong Wang, Albert J. Kooistra, Nick Bushby, Sebastiaan Kuhne, Jelle Van Den Bor, Michael J. Waring, Chris De Graaf, Iwan J. De Esch, Henry F. Vischer, Robert J. Sheppard, Maikel Wijtmans, Rob Leurs*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Drug-target binding kinetics are an important predictor of in vivo drug efficacy, yet the relationship between ligand structures and their binding kinetics is often poorly understood. We show that both rupatadine (1) and desloratadine (2) have a long residence time at the histamine H1 receptor (H1R). Through development of a [3H]levocetirizine radiolabel, we find that the residence time of 1 exceeds that of 2 more than 10-fold. This was further explored with 22 synthesized rupatadine and desloratadine analogues. Methylene-linked cycloaliphatic or β-branched substitutions of desloratadine increase the residence time at the H1R, conveying a longer duration of receptor antagonism. However, cycloaliphatic substituents directly attached to the piperidine amine (i.e., lacking the spacer) have decreased binding affinity and residence time compared to their methylene-linked structural analogues. Guided by docking studies, steric constraints within the binding pocket are hypothesized to explain the observed differences in affinity and binding kinetics between analogues.

Original languageEnglish
Pages (from-to)6630-6644
Number of pages15
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - 25 Jul 2019


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