Emerging strategies targeting CB₂ cannabinoid receptor: Biased agonism and allosterism

During these last years, the CB₂ cannabinoid receptor has emerged as a potential anti-inflammatory target in diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, ischemic stroke, autoimmune diseases, osteoporosis, and cancer. However, the development of clinically useful CB₂ agonists reveals to be very challenging. Allosterism and biased-signaling mechanisms at CB₂ receptor may offer new avenues for the development of improved CB₂ receptor-targeted therapies. Although there has been some exploration of CB₁ receptor activation by new CB₁ allosteric or biased-signaling ligands, the CB₂ receptor is still at initial stages in this domain. In an effort to understand the molecular basis behind these pharmacological approaches, we have analyzed and summarized the structural data reported so far at CB₂ receptor.