In vitro and in vivo characterization of A‐796260: a selective cannabinoid CB2receptor agonist exhibiting analgesic activity in rodent pain models

Abstract

Background and purpose: Selective cannabinoid CB 2 receptor agonists have demonstrated analgesic activity across multiple preclinical pain models. AM1241 is an indole derivative that exhibits high affinity and selectivity for the CB 2 binding site and broad spectrum analgesic activity in rodent models, but is not an antagonist of CB 2in vitro functional assays. Additionally, its analgesic effects are μ‐opioid receptor‐dependent. Herein, we describe the in vitro and in vivo pharmacological properties of A‐796260, a novel CB 2 agonist. Experimental approach: A‐796260 was characterized in radioligand binding and in vitro functional assays at rat and human CB 1 and CB 2 receptors. The behavioural profile of A‐796260 was assessed in models of inflammatory, post‐operative, neuropathic, and osteoarthritic (OA) pain, as well as its effects on motor activity. The receptor specificity was confirmed using selective CB 1, CB 2 and μ‐opioid receptor antagonists. Key results: A‐796260 exhibited high affinity and agonist efficacy at human and rat CB 2 receptors, and was selective for the CB 2 vs CB 1 subtype. Efficacy in models of inflammatory, post‐operative, neuropathic and OA pain was demonstrated, and these activities were selectively blocked by CB 2, but not CB 1 or μ‐opioid receptor‐selective antagonists. Efficacy was achieved at doses that had no significant effects on motor activity. Conclusions and implications: These results further confirm the therapeutic potential of CB 2 receptor‐selective agonists for the treatment of pain. In addition, they demonstrate that A‐796260 may be a useful new pharmacological compound for further studying CB 2 receptor pharmacology and for evaluating its role in the modulation of pain. British Journal of Pharmacology(2008)153, 390–401; doi:10.1038/sj.bjp.0707568; published online 12 November 2007