Department of Biology, University of Nebraska-Kearney, United States.
Department of Chemistry, University of Nebraska-Kearney, United States.
Pharmacol Res. 2021 Mar;165:105410. doi: 10.1016/j.phrs.2020.105410. Epub 2021 Jan 2.
All four of the adenosine receptor (AR) subtypes mediate pain and have been targeted by pharmacologists to generate new therapeutics for chronic pain. The vanilloid phytochemicals, which include curcumin, capsaicin, and gingerol, have been shown to alleviate pain. However, there is little to no literature on the interaction of vanilloid phytochemicals with ARs. In this study, photochemical methods were used to generate a novel isomer of curcumin (cis-trans curcumin or CTCUR), and the interactions of both curcumin and CTCUR with the two G-linked AR subtypes were studied. Competitive binding assays, docking analysis, and confocal fluorescence microscopy were performed to measure binding affinity; cell survival assays were used to measure toxicity; and cAMP assays were performed to measure receptor activation. Competitive binding results indicated that CTCUR binds to both AR A and AR A with K values of 5 μM and 7 μM, respectively, which is consistent with our docking results. Fluorescence microscopy data also shows binding for A and A. Cell survival results show that CTCUR and CUR are nontoxic at the tested concentrations in these cell lines. Overall, our results suggest that vanilloid phytochemicals may be slightly modified to increase interaction with G-ARs, and thereby can be further explored to provide a novel class of non-opioid antinociceptives.
所有四种腺苷受体（AR）亚型都介导疼痛，并已被药理学家靶向，以产生用于慢性疼痛的新疗法。香草素植物化学物质，包括姜黄素、辣椒素和姜辣素，已被证明可以缓解疼痛。然而，关于香草素植物化学物质与 AR 的相互作用的文献很少。在这项研究中，光化学方法被用于生成姜黄素的一种新异构体（顺式-反式姜黄素或 CTCUR），并研究了姜黄素和 CTCUR 与两种 G 链接的 AR 亚型的相互作用。竞争性结合测定、对接分析和共聚焦荧光显微镜用于测量结合亲和力；细胞存活测定用于测量毒性；cAMP 测定用于测量受体激活。竞争性结合结果表明，CTCUR 分别以 5 μM 和 7 μM 的 K 值与 AR A 和 AR A 结合，这与我们的对接结果一致。荧光显微镜数据也显示 A 和 A 的结合。细胞存活结果表明，在这些细胞系中，CTCUR 和 CUR 在测试浓度下均无毒性。总的来说，我们的结果表明，香草素植物化学物质可能经过轻微修饰以增加与 G-AR 的相互作用，因此可以进一步探索以提供一类新型非阿片类镇痛药。
