Route to Prolonged Residence Time at the Histamine H1 Receptor: Growing from Desloratadine to Rupatadine
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Route to Prolonged Residence Time at the Histamine H1 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.
In: Journal of Medicinal Chemistry, Vol. 62, No. 14, 25.07.2019, p. 6630-6644.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Route to Prolonged Residence Time at the Histamine H1 Receptor
T2 - Growing from Desloratadine to Rupatadine
AU - Bosma, Reggie
AU - Wang, Zhiyong
AU - Kooistra, Albert J
AU - Bushby, Nick
AU - Kuhne, Sebastiaan
AU - van den Bor, Jelle
AU - Waring, Michael J
AU - de Graaf, Chris
AU - de Esch, Iwan J
AU - Vischer, Henry F
AU - Sheppard, Robert J
AU - Wijtmans, Maikel
AU - Leurs, Rob
PY - 2019/7/25
Y1 - 2019/7/25
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.9b00447
DO - 10.1021/acs.jmedchem.9b00447
M3 - Journal article
C2 - 31274307
VL - 62
SP - 6630
EP - 6644
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 14
ER -
ID: 235971868