Lookup NU author(s): Professor Mike Waring
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We report on the synthesis and biological evaluation of a series of 1,2-diarylimidazol-4-carboxamide derivatives developed as CB1 receptor antagonists. These were evaluated in a radioligand displacement binding assay, a [35S]GTPγS binding assay, and in a competition association assay that enables the relatively fast kinetic screening of multiple compounds. The compounds show high affinities and a diverse range of kinetic profiles at the CB1 receptor, and their structure-kinetic relationships (SKRs) were established. Using the recently resolved hCB1receptor crystal structures, we also performed a modelling study that sheds light on the crucial interactions for both the affinity and dissociation kinetics of this family of ligands. We provide evidence that, next to affinity, additional knowledge of binding kinetics is useful for selecting new hCB1 receptor antagonists in the early phases of drug discovery.
Author(s): Xia L, de Vries H, Lenselink EB, Louvel J, Waring MJ, Cheng L, Pahlén S, Petersson MJ, Schell P, Olsson RI, Heitman LH, Sheppard RJ, IJzerman AP
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Print publication date: 14/12/2017
Online publication date: 07/11/2017
Acceptance date: 13/06/2017
Date deposited: 25/06/2018
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
Publisher: American Chemical Society
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