- W. Guba
- M. Nazaré
- U. Grether
- New tools to interrogate endocannabinoid signalling
- 76: 89-167
The G-protein coupled cannabinoid type 2 (CB2) receptor is a key element of the endocannabinoid system (ECS). EC/CB2 receptor signaling has tremendous therapeutic potential in some of the major pathologies affecting humans. CB2 receptor agonism exerts anti-inflammatory and tissue-protective effects in preclinical animal models of cardiovascular, gastrointestinal, liver, kidney lung and neurodegenerative disorders. Existing molecules targeting CB2R can be sub-divided into endocannabinoids and related fatty acid derivatives, phytocannabinoids and synthetic CB2 receptor ligands that possess various degrees of potency on CB2R and selectivity against the cannabinoid type 1 receptor (CB1R). While early CB2R ligands suffer from high lipophilicity, low solubility and tight plasma protein binding resulting in high in vivo clearance, medicinal chemists overcame these initial issues and provided highly potent, selective, drug-like and developable assets from structurally diverse chemotypes, which is reflected by a number of ongoing promising clinical trials. These achievements are complemented by the discovery of allosteric ligands and various high-quality chemical probes that will enable a better understanding of CB2R expression and mechanism of action, thereby unlocking the receptor's full therapeutic potential. In this review we describe the current knowledge on CB2R ligands by highlighting representative key molecules from different chemotypes and relevant results from pharmacological and clinical studies.