Novel series of CB2 selective antagonists for the treatment of autoimmune disorders: Synthesis, functional evaluation and ligand-steered modeling

PETROV, R.R.; PHATAK, SHARANGDHAR S; ASTRUC-DIAZ, FANNY; CAVASOTTO, CLAUDIO N.; DIAZ, PHILIPPE

Boston, MA

Conferencia; 240th National Meeting of the American-Chemical-Society; 2010

The cannabinoid receptor CB2 has emerged as a new target for the treatment of pain without the CB1 mediated psychotropic side effects. Emerging evidence suggests that CB2 receptor blockage is a promising therapeutic approach for more effective treatment of autoimmune disorders. Two series of novel cannabinoid modulators have been synthesized using two different heterocyclic scaffolds. In vitro binding and functional assays were used to identify highly potent and selective CB2 agonists and antagonists. Fluorescent ligands were prepared based on the new analogs. More importantly, we were able to shift from CB2 agonist to CB2 antagonist functional activity by using a ?chemical switch?. Using the ligand-steered homology modeling method two models for CB2 were developed. The models successfully rationalized the structure-activity relationship data and predicted binding modes for both series of compounds. Details about the synthesis, CB1 and CB2 receptors structure-activity relationships, will be presented