Discovery and optimization of selective CB₂ receptor agonists

Abstract

This Doctoral Thesis describes the design, development, and the pharmacological characterization of new CB2R selective agonists, thus contributing to the discovery of new therapeutic agents for the treatment of inflammation and cancer. Taking two families of designer drugs as a model, we synthesized and pharmacologically characterized a collection of CB1-CB2 dual agonists routinely used as designer drugs. This study allowed us to identify new SAR trends and discover their toxic effect on primary neuronal cells. Based on this study, we developed an MCR-assisted pharmacomodulation process that enabled us to explore the structural features governing ligand binding and to discover new series of selective CB2R agonists devoid of dual ligands’ psychoactive effects. Several of these ligands show excellent affinity and selectivity for the CB2R, modulating it in an enantiospecific manner and exhibiting biased signaling. Finally, we demonstrated the anti-inflammatory and anticancer activity of herein discovered CB2R ligands.