Modelling the Cannabinoid 2 Receptor and Structure Based Studies of Agonist/antagonist Molecular Switches

CAVASOTTO, CLAUDIO N.; SPINOSA, M.; AUCAR, MARÍA G.; DIAZ, PHILIPPE

Camerino

Simposio; 33rd Camerino-Cyprus Symposium "Receptor Chemistry: Reality and Vision"; 2016

There is a growinginterest in using agonists of the cannabinoid receptor 2 (CB2) for the treatmentof neuropathic pain.  Although thestructure-based discovery and design of small-molecule modulators is hamperedby the lack of CB2 experimental crystal structures, the sustained developmentof antagonist, inverse-agonist, and agonist-bound G Protein-Coupled Receptors(GPCRs) structures clears the way for reliable homology models (1). Recently,structure-based efforts led to the discovery of non-selective and selectivetricyclic carbazole CB2 agonists with activity in the nanomolar range (2).  These promising results prompted us to buildimproved CB2 models, using different modelling strategies, and withligand-steered optimized binding sites. Our models were validated using published mutagenesis data andsmall-scale high-throughput docking using the GPCR Ligand Library (GLL) and theGPCR Decoy Database (GDD) (3).  Theresults of our molecular modelling support the successful rationalization ofthe structure-activity relationship data for agonist and antagonist ligands,especially of a remarkably efficient switch from agonistic to antagonisticbehaviour occurred when introducing a methoxy moiety into the series of thesenovel compounds. (1)           Cavasotto, C. N.;Palomba, D. Chem. Commun. 2015, 51, 13576-13594.(2)           Petrov, R. R.;Knight, L.; Chen, S. R.; Wager-Miller, J.; McDaniel, S. W.; Diaz, F.; Barth,F.; Pan, H. L.; Mackie, K.; Cavasotto, C. N.; Diaz, P. Eur. J. Med. Chem. 2013,69, 881-907.(3)           Gatica, E. A.;Cavasotto, C. N. J. Chem. Inf. Model.2012, 52, 1-6.