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

被引:74
作者
Bingham, B.
Jones, P. G.
Uveges, A. J.
Kotnis, S.
Lu, P.
Smith, V. A.
Sun, S-C
Resnick, L.
Chlenov, M.
He, Y.
Strassle, B. W.
Cummons, T. A.
Piesla, M. J.
Harrison, J. E.
Whiteside, G. T.
Kennedy, J. D.
机构
[1] Wyeth Res, Neurosci Discovery Res, Princeton, NJ 08543 USA
[2] Wyeth Res, Chem & Screening Sci, Princeton, NJ 08543 USA
[3] Wyeth Res, Discovery Analyt Chem, Princeton, NJ 08543 USA
关键词
AM1241; cannabinoid; CB2; enantiomer; protean agonism;
D O I
10.1038/sj.bjp.0707303
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 enantiomers in vitro and in vivo. Experimental approach: Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB2 receptors. 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 compounds in 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 CB2 receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB2 receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB2 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 CB2 receptors. Conclusions and implications: These findings constitute the first in vitro functional assessment of R, S-AM1241 at rodent CB2 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 CB2 agonist enantiomer of AM1241, is consistent with previous observations that CB2 agonists are effective in relief of pain.
引用
收藏
页码:1061 / 1070
页数:10
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