These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
Preprints are manuscripts made publicly available before they have been submitted for formal peer review and publication. They might contain new research findings or data. Preprints can be a draft or final version of an author's research but must not have been accepted for publication at the time of submission.
submitted on 30.09.2019 and posted on 01.10.2019by Matthias V. Westphal, Roman C. Sarott, Elisabeth A. Zirwes, Anja Osterwald, Wolfgang Guba, Christoph Ullmer, Uwe Grether, Erick M. Carreira
The endocannabinoid (eCB) system is implied in
various human diseases ranging from central nervous system to autoimmune
disorders. Cannabinoid receptor 2 (CB2R) is an integral component of
the eCB system. Yet, the downstream effects elicited by this G protein-coupled
receptor upon binding of endogenous or synthetic ligands are insufficiently
understood—likely due to the limited arsenal of reliable biological and
chemical tools. Herein,
we report the design and synthesis of CB2R-selective cannabinoids along with their in vitro pharmacological
characterization (binding and functional studies). They combine structural
features of HU-308 and AM841 to give chimeric ligands that emerge as potent CB2R agonists with high selectivity over the closely related cannabinoid
receptor 1 (CB1R). The synthesis work includes convenient preparation of
substituted resorcinols often found in cannabinoids. The utility of the
synthetic cannabinoids in this study is showcased by preparation of the most
selective high-affinity fluorescent probe for CB2R to date.