Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers

Br J Pharmacol. 2007 Aug;151(7):1061-70. doi: 10.1038/sj.bjp.0707303. Epub 2007 Jun 4.


Background and purpose: Racemic (R,S) AM1241 is a cannabinoid receptor 2 (CB(2))-selective aminoalkylindole with antinociceptive efficacy in animal pain models. The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo.

Experimental approach: Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB(2) receptors. Inhibition of cAMP was assayed using intact CB(2)-expressing cells. A mouse model of visceral pain (para-phenylquinone, PPQ) and a rat model of acute inflammatory pain (carrageenan) were employed to characterize the compounds in vivo.

Key results: In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB(2), but an inverse agonist at rat and mouse CB(2) receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. Antagonist blockade demonstrated that the in vivo effects of S-AM1241 were mediated by CB(2) receptors.

Conclusions and implications: These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB(2) receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems and in vivo. The greater antinociceptive efficacy of S-AM1241, the functional CB(2) agonist enantiomer of AM1241, is consistent with previous observations that CB(2) agonists are effective in relief of pain.

MeSH terms

  • Analgesics / pharmacology
  • Animals
  • Benzoxazines / pharmacology
  • CHO Cells
  • Calcium Channel Blockers / pharmacology
  • Camphanes / pharmacology
  • Cannabinoids / chemistry
  • Cannabinoids / metabolism
  • Cannabinoids / pharmacology
  • Carrageenan / toxicity
  • Colforsin / pharmacology
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / metabolism
  • Cyclohexanols / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / physiopathology
  • Hyperalgesia / prevention & control
  • Indoles / pharmacology
  • Mice
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Protein Binding / drug effects
  • Pyrazoles / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, Cannabinoid, CB2 / agonists*
  • Receptor, Cannabinoid, CB2 / genetics
  • Receptor, Cannabinoid, CB2 / metabolism
  • Species Specificity
  • Stereoisomerism
  • Tritium


  • AM 1241
  • Analgesics
  • Benzoxazines
  • Calcium Channel Blockers
  • Camphanes
  • Cannabinoids
  • Cyclohexanols
  • Indoles
  • Morpholines
  • Naphthalenes
  • Pyrazoles
  • Receptor, Cannabinoid, CB2
  • SR 144528
  • Tritium
  • Colforsin
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • 3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol
  • Carrageenan
  • Cyclic AMP
  • iodopravadoline