Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers
Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers
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DOI：
10.1038/sj.bjp.0707303
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发表时间：
2007-08-01
影响因子：
7.3
通讯作者：
Kennedy, J. D.
中科院分区：
文献类型：
--
作者：
Bingham, B.;Jones, P. G.;Kennedy, J. D.
背景与目的：外消旋(R，S)AM1241是一种对大麻素受体2(CB2)有选择性的氨基烷基吲哚，在动物疼痛模型中具有抗伤害性作用。本研究的目的是提供R，S-AM1241及其拆分对映体的体内外特性。实验方法：利用表达重组人、大鼠和小鼠CB2受体的细胞膜进行竞争结合分析。用完整的CB2表达细胞检测cAMP的抑制作用。用小鼠内脏痛模型(对苯二酚)和大鼠急性炎症性疼痛模型(卡拉胶)对化合物进行了体内表征。关键结果：在cAMP抑制实验中，R，S-AM1241在人CB2受体上是激动剂，而在大鼠和小鼠CB2受体上是反向激动剂。R-AM1241与三种CB2受体的亲和力均比S-AM1241高40多倍，并显示出与外消旋体相似的功能图谱。相反，S-AM1241是所有三种CB2受体的激动剂。在疼痛模型中，S-AM1241的止痛效果优于R-AM1241和消旋体。结论和意义：本研究首次对R，S-AM1241在啮齿动物CB2受体上的功能进行了研究，并首次在重组细胞系统和体内对AM1241对映体进行了表征。AM1241的功能性CB2激动剂对映体S-AM1241具有更强的抗伤害性作用，这与以往CB2激动剂具有止痛作用的观察结果一致。
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.