Cannabinoid CB₂ receptor orthologues; in vitro function and perspectives for preclinical to clinical translation

Cannabinoid CB₂ receptor agonists are in development as therapeutic agents, including for immune modulation and pain relief. Despite promising results in rodent preclinical studies, efficacy in human clinical trials has been marginal to date. Fundamental differences in ligand engagement and signalling responses between the human CB₂ receptor and preclinical model species orthologues may contribute to mismatches in functional outcomes. This is a tangible possibility for the CB₂ receptor in that there is a relatively large degree of primary amino acid sequence divergence between human and rodent. Here, we summarise CB₂ receptor gene and protein structure, assess comparative molecular pharmacology between CB₂ receptor orthologues, and review the current status of preclinical to clinical translation for drugs targeted at the CB₂ receptor, focusing on comparisons between human, mouse and rat receptors. We hope that raising wider awareness of, and proposing strategies to address, this additional challenge in drug development will assist in ongoing efforts toward successful therapeutic translation of drugs targeted at the CB₂ receptor. LINKED ARTICLES: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.