Species‐specificin vitropharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers

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Abstract
Background and purpose: Racemic (R,S) AM1241 is a cannabinoid receptor 2 (CB2)‐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 enantiomersin vitroandin vivo.Experimental approach: Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB2receptors. Inhibition of cAMP was assayed using intact CB2‐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 compoundsin vivo.Key results: In cAMP inhibition assays, R,S‐AM1241 was found to be an agonist at human CB2, but an inverse agonist at rat and mouse CB2receptors. R‐AM1241 bound with more than 40‐fold higher affinity than S‐AM1241, to all three CB2receptors and displayed a functional profile similar to that of the racemate. In contrast, S‐AM1241 was an agonist at all three CB2receptors. In pain models, S‐AM1241 was more efficacious than either R‐AM1241 or the racemate. Antagonist blockade demonstrated that thein vivoeffects of S‐AM1241 were mediated by CB2receptors.Conclusions and implications: These findings constitute the firstin vitrofunctional assessment of R,S‐AM1241 at rodent CB2receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems andin vivo. The greater antinociceptive efficacy of S‐AM1241, the functional CB2agonist enantiomer of AM1241, is consistent with previous observations that CB2agonists are effective in relief of pain.British Journal of Pharmacology(2007)151, 1061–1070; doi:10.1038/sj.bjp.0707303