Route to Prolonged Residence Time at the Histamine H1 Receptor: Growing from Desloratadine to Rupatadine.
J Med Chem
; 62(14): 6630-6644, 2019 07 25.
Article
em En
| MEDLINE
| ID: mdl-31274307
ABSTRACT
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 ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Receptores Histamínicos H1
/
Loratadina
/
Ciproeptadina
/
Antagonistas dos Receptores Histamínicos H1
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Ano de publicação:
2019
Tipo de documento:
Article