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Structure-affinity Relationships and Structure-kinetic Relationships of 1,2-Diarylimidazol-4-carboxamide Derivatives as Human Cannabinoid 1 Receptor Antagonists

Lookup NU author(s): Professor Mike Waring



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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.

Publication metadata

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

Year: 2017

Volume: 60

Issue: 23

Pages: 9545-9564

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


DOI: 10.1021/acs.jmedchem.7b00861


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