In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB₂ receptor?

Abstract

Background and purpose: The CB 2 receptor has been proposed as a novel target for the treatment of pain, and CB 2 receptor agonists defined in in vitro assays have demonstrated analgesic activity in animal models. Based on its in vivo analgesic efficacy, AM1241 has been classified as a CB 2 -selective agonist. However, in vitro characterization of AM1241 in functional assays has not been reported. Experimental approach: In this study, AM1241 was characterized across multiple in vitro assays employing heterologous recombinant receptor expression systems to assess its binding potencies at the human CB 2 and CB 1 receptors and its functional efficacies at the human CB 2 receptor. 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 CB 2 receptor. 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 in in vitro assays may not predict in vivo activities.

Retraction: The Dietary Polyphenols trans-Resveratrol and Curcumin Selectively Bind Human CB1 Cannabinoid Receptors with Nanomolar Affinities and Function as Antagonists/Inverse Agonists

“…These data suggest that the polyphenols tested might act as protean agonists at CB1 receptors, similar to that recently described for the CB2 ligand AM-1241 (Yao et al, 2006). A protean agonist is a compound that changes its apparent intrinsic activity to exhibit agonist, antagonist, or inverse agonist activity at the same receptor, depending on the specific assay systems employed for detection.…”

CB2Cannabinoid Receptors as a Therapeutic Target—What Does the Future Hold?

“…Subsequent work by a number of groups has confirmed and extended these studies with a variety of structurally distinct CB 2 agonists (Murineddu et al, 2013). Generally, the field has moved away from AM1241, as AM1241 appears to engage a unique endogenous opioid-mediated component for its analgesia (Ibrahim et al, 2005;Whiteside et al, 2005); its enantiomers have different actions and its efficacy is species-dependent (Bingham et al, 2007); and it is a low-efficacy agonist, as it exhibits protean agonism (Yao et al, 2006).…”

Prevention of Fibrosis Progression in CCl4-Treated Rats: Role of the Hepatic Endocannabinoid and Apelin Systems

“…AM1241 is among the most selective receptor agonists currently available. For CB2 and CB1 receptors, the binding affinity (K i ) is 3.4 and 239.4 nM, respectively, and previous experiments have provided pharmacological and biochemical evidence that AM1241 selectively activates the CB2 receptor in vivo in mice, rats, and human cell lines (Malan et al, 2001;Ibrahim et al, 2003;Yao et al, 2006). The absence of central effects induced by CB2 agonism has been the major rationale to propose this mechanism as an antifibrogenic therapy.…”