School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.
Pharmacol Res. 2010 Apr;61(4):349-54. doi: 10.1016/j.phrs.2009.11.011. Epub 2009 Dec 2.
We have previously developed quinolone-3-carboxamides with the aim of obtaining new ligands for both cannabinoid receptors, CB1 and CB2. Our preliminary screening led to the identification of cannabinoid receptor ligands characterized by high affinity and, in some cases, also selectivity for CB(2) receptors. Specifically, three compounds, 1, 2 and 3 showed high affinity for CB2 as well as high selectivity over CB1 receptors. In addition, the activity shown by 1 against the formalin-induced nocifensive response in mice, reported in our previous paper, suggests that quinolone-3-carboxamides possess anti-nociceptive properties. In the present work, we have performed functional in vitro bioassays with the aim of investigating the functional activity in the [35S]GTPgammaS binding assay of the other two compounds that, like 1, behave as CB2 selective ligands, and their potential analgesic actions in vivo. We found that both 2 and 3 behave in vitro as CB2 inverse agonists and are able to decrease nociceptive behaviour in the late phase of the formalin test only at the highest dose tested, although, at lower doses, they prevent the anti-nociceptive effects of a selective CB2 partial agonist in the formalin test. These results identify in 2 and 3 two novel, potent and selective CB2 antagonists/inverse agonists and confirm previous reports in the literature that, in addition to agonists at cannabinoid CB2 receptors, also inverse agonists/antagonists at these receptors show promise as anti-inflammatory agents.
我们之前开发了喹诺酮-3-甲酰胺,旨在获得大麻素受体 CB1 和 CB2 的新配体。我们的初步筛选导致了识别大麻素受体配体的特征是高亲和力,在某些情况下,也对 CB(2)受体具有选择性。具体来说,三种化合物 1、2 和 3 对 CB2 具有高亲和力,对 CB1 受体具有高选择性。此外,我们之前的论文中报道了化合物 1 对小鼠福尔马林诱导的伤害性反应的活性,表明喹诺酮-3-甲酰胺具有抗伤害性特性。在本工作中,我们进行了功能体外生物测定,目的是研究其他两种化合物在[35S]GTPγS 结合测定中的功能活性,这两种化合物与 1 一样,表现为 CB2 选择性配体,以及它们在体内的潜在镇痛作用。我们发现,化合物 2 和 3 在体外均表现为 CB2 反向激动剂,仅在最高测试剂量下才能降低福尔马林试验的晚期伤害性行为,尽管在较低剂量下,它们可预防选择性 CB2 部分激动剂在福尔马林试验中的抗伤害性作用。这些结果确定了化合物 2 和 3 为两种新型、有效且选择性的 CB2 拮抗剂/反向激动剂,并证实了文献中的先前报道,即除了大麻素 CB2 受体激动剂外,这些受体的反向激动剂/拮抗剂也有望作为抗炎剂。