In vitropharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2receptor?

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Abstract
Background and purpose: The CB2receptor has been proposed as a novel target for the treatment of pain, and CB2receptor agonists defined inin vitroassays have demonstrated analgesic activity in animal models. Based on itsin vivoanalgesic efficacy, AM1241 has been classified as a CB2‐selective agonist. However,in vitrocharacterization of AM1241 in functional assays has not been reported.Experimental approach: In this study, AM1241 was characterized across multiplein vitroassays employing heterologous recombinant receptor expression systems to assess its binding potencies at the human CB2and CB1receptors and its functional efficacies at the human CB2receptor.Key results: AM1241 exhibited distinct functional properties depending on the assay conditions employed, a unique profile in contrast to those of the agonist CP 55,940 and the inverse agonist SR144528. AM1241 displayed neutral antagonist activities in FLIPR and cyclase assays. However, when cyclase assays were performed using lower forskolin concentrations for stimulation, AM1241 exhibited partial agonist efficacy. In addition, it behaved as a partial agonist in ERK (or MAP) kinase assays.Conclusions and implications: The unusual phenomenon of inconsistent functional efficacies suggests that AM1241 is a protean agonist at the CB2receptor. We postulate that functional efficacies displayed by protean agonists in various assay systems may depend on the levels of receptor constitutive activities exhibited in the assay systems, and therefore, efficacies observed inin vitroassays may not predictin vivoactivities.British Journal of Pharmacology(2006)149, 145–154. doi:10.1038/sj.bjp.0706838