172219-28-2Relevant academic research and scientific papers
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
, p. 6630 - 6644 (2019/08/20)
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.
Synthesis of [2-{(4-chlorophenyl)(4-[125I]iodophenyl)} methoxyethyl]-1-piperidine-3-carboxylic acid, [125I]CIPCA: A potential radiotracer for GABA uptake sites
Van Dort,Gildersleeve,Wieland
, p. 961 - 971 (2007/10/02)
The synthesis of racemic [2-{(4-Chlorophenyl)(4-iodophenyl)} methoxyethyl]-1-piperidine-3-carboxylic acid, (CIPCA) and its radioiodinated analog [125]CIPCA is described. CIPCA was synthesized from 4-iodobenzoyl chloride in five steps in 16% overall yield. Ammonium sulfate catalyzed solid-state isotopic exchange of CIPCA with Na125I provided [125I]CIPCA in 34% isolated radiochemical yield at a specific activity of 118 Ci/mmol. [125I]CIPCA demonstrated moderate brain extraction and good in vivo radiostability in preliminary biodistribution studies conducted in CD-1 mice. [125I]CIPCA is a potentially useful radiotracer for study of the GABA uptake system.
