title: In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor?
abstract: OBJECTIVE
  The CB2 receptor has been proposed as a novel target for the treatment of pain, and CB2 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 CB2-selective agonist. However, in vitro characterization of AM1241 in functional assays has not been reported.
  
  
  METHODS
  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 CB2 and CB1 receptors and its functional efficacies at the human CB2 receptor.
  
  
  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
  The unusual phenomenon of inconsistent functional efficacies suggests that AM1241 is a protean agonist at the CB2 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.
authors.affiliation: Neuroscience Disease Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. betty.yao@abbott.com
authors.forename: B B
authors.initials: BB
authors.lastname: Yao
authors.forename: S
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Y
authors.initials: Y
authors.lastname: Fan
authors.forename: T R
authors.initials: TR
authors.lastname: Garrison
authors.forename: A V
authors.initials: AV
authors.lastname: Daza
authors.forename: G K
authors.initials: GK
authors.lastname: Grayson
authors.forename: B A
authors.initials: BA
authors.lastname: Hooker
authors.forename: M J
authors.initials: MJ
authors.lastname: Dart
authors.forename: J P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: M D
authors.initials: MD
authors.lastname: Meyer
mesh_terms: D002186:Cannabinoids / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*
chemical_list: C439263:AM 1241; D002186:Cannabinoids; D043885:Receptor, Cannabinoid, CB2