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Route to Prolonged Residence Time at the Histamine H1 Receptor: Growing from Desloratadine to Rupatadine

Lookup NU author(s): Professor Mike Waring



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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.

Publication metadata

Author(s): Bosma R, Wang Z, Kooistra AJ, Bushby N, Kuhne S, van den Bor J, Waring MJ, de Graaf C, de Esch IJ, Vischer HF, Sheppard RJ, Wijtmans M, Leurs R

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2019

Volume: 62

Issue: 14

Pages: 6630-6644

Online publication date: 20/06/2019

Acceptance date: 20/06/2019

Date deposited: 02/08/2019

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/acs.jmedchem.9b00447


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