Abstract
Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealised, therapeutic potential. Promising preclinical data supports the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopoeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such not optimal for clinical application due to unfavourable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to ‘drug-like’ properties and a few such compounds have now undergone clinical trial. We review the current state of CB2 ligand development and progress in optimising physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds.
Cannabinoid Receptor 2 (CB2) is a promising therapeutic target, particularly for inflammatory disorders and pain; however, clinical trials to date have been unsuccessful.Medicinal chemistry efforts have produced selective ligands with a wide range of core scaffolds. Optimisation for drug-like properties and oral administration has been demonstrated to be feasible, but few such compounds have been tested clinically to date.Recent crystal and cryo-EM structures are expected to facilitate rational ligand development and further optimisation.Although CB2 ligands can produce functional selectivity (bias) of signalling responses, few new classes of ligand have been studied in this context. The physiological relevance of CB2 signalling bias, and subcellular spatial organisation of CB2 signalling, remain to be elucidated.