Cannabinoid Receptor 2 (CB2) Orthologue In Vitro Function and Perspectives for Preclinical to Clinical Translation

Br J Pharmacol. 2023 Jun 22. doi: 10.1111/bph.16172. Online ahead of print.

ABSTRACT

Cannabinoid receptor 2 (CB2 ) agonists are in development as therapeutics, 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 human CB2 and preclinical model species orthologues may contribute to mismatches in functional outcomes. This is a tangible possibility for CB2 in that there is a relatively large degree of primary amino acid sequence divergence between human and rodent. Here, we summarise CB2 gene and protein structure, assess comparative molecular pharmacology between CB2 orthologues, and review the current status of preclinical to clinical translation for CB2 -targeted drugs, focusing on comparisons between human, mouse and rat CB2 . We hope that raising wider awareness of, and proposing strategies to address, this additional challenge in CB2 drug development will assist in ongoing efforts toward successful therapeutic translation of CB2 -targeted drugs.

PMID:37349984 | DOI:10.1111/bph.16172