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Route to Prolonged Residence Time at the Histamine H(1) Receptor: Growing from Desloratadine to Rupatadine
[Image: see text] 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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750840/ https://www.ncbi.nlm.nih.gov/pubmed/31274307 http://dx.doi.org/10.1021/acs.jmedchem.9b00447 |
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author | Bosma, Reggie Wang, Zhiyong Kooistra, Albert J. Bushby, Nick Kuhne, Sebastiaan van den Bor, Jelle Waring, Michael J. de Graaf, Chris de Esch, Iwan J. Vischer, Henry F. Sheppard, Robert J. Wijtmans, Maikel Leurs, Rob |
author_facet | Bosma, Reggie Wang, Zhiyong Kooistra, Albert J. Bushby, Nick Kuhne, Sebastiaan van den Bor, Jelle Waring, Michael J. de Graaf, Chris de Esch, Iwan J. Vischer, Henry F. Sheppard, Robert J. Wijtmans, Maikel Leurs, Rob |
author_sort | Bosma, Reggie |
collection | PubMed |
description | [Image: see text] 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 H(1) receptor (H(1)R). Through development of a [(3)H]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 H(1)R, 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. |
format | Online Article Text |
id | pubmed-6750840 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-67508402019-09-19 Route to Prolonged Residence Time at the Histamine H(1) Receptor: Growing from Desloratadine to Rupatadine Bosma, Reggie Wang, Zhiyong Kooistra, Albert J. Bushby, Nick Kuhne, Sebastiaan van den Bor, Jelle Waring, Michael J. de Graaf, Chris de Esch, Iwan J. Vischer, Henry F. Sheppard, Robert J. Wijtmans, Maikel Leurs, Rob J Med Chem [Image: see text] 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 H(1) receptor (H(1)R). Through development of a [(3)H]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 H(1)R, 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. American Chemical Society 2019-06-20 2019-07-25 /pmc/articles/PMC6750840/ /pubmed/31274307 http://dx.doi.org/10.1021/acs.jmedchem.9b00447 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. |
spellingShingle | Bosma, Reggie Wang, Zhiyong Kooistra, Albert J. Bushby, Nick Kuhne, Sebastiaan van den Bor, Jelle Waring, Michael J. de Graaf, Chris de Esch, Iwan J. Vischer, Henry F. Sheppard, Robert J. Wijtmans, Maikel Leurs, Rob Route to Prolonged Residence Time at the Histamine H(1) Receptor: Growing from Desloratadine to Rupatadine |
title | Route to Prolonged
Residence Time at the Histamine
H(1) Receptor: Growing from Desloratadine to Rupatadine |
title_full | Route to Prolonged
Residence Time at the Histamine
H(1) Receptor: Growing from Desloratadine to Rupatadine |
title_fullStr | Route to Prolonged
Residence Time at the Histamine
H(1) Receptor: Growing from Desloratadine to Rupatadine |
title_full_unstemmed | Route to Prolonged
Residence Time at the Histamine
H(1) Receptor: Growing from Desloratadine to Rupatadine |
title_short | Route to Prolonged
Residence Time at the Histamine
H(1) Receptor: Growing from Desloratadine to Rupatadine |
title_sort | route to prolonged
residence time at the histamine
h(1) receptor: growing from desloratadine to rupatadine |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750840/ https://www.ncbi.nlm.nih.gov/pubmed/31274307 http://dx.doi.org/10.1021/acs.jmedchem.9b00447 |
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