Laboratório de Farmacologia e Terapêutica Experimental, Faculdade de Farmácia, Universidade Federal da Bahia, Salvador CEP 40 170-115, Brazil.
Laboratório de Engenharia Tecidual e Imunofarmacologia, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador CEP 40 296-710, Brazil.
Int J Mol Sci. 2021 Mar 26;22(7):3413. doi: 10.3390/ijms22073413.
The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK's mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.
疼痛的适当药物控制对患者和医疗保健提供者来说是一个持续的挑战。即使是最广泛用于治疗疼痛的药物，对一些患者，特别是那些患有慢性疼痛的患者来说，仍然无效或不安全。含有色酮骨架的物质表现出多种生物活性，包括镇痛作用。本工作首次报道了 5-O-甲基 cneorumchromone K（5-CK）的中枢介导的镇痛活性。在小鼠的冷板和尾部闪烁试验中，5-CK 诱导的镇痛作用呈剂量依赖性，持续时间更长，效果比吗啡更强。阿片受体拮抗剂纳洛酮不能逆转 5-CK 诱导的镇痛作用。拓扑描述符（指纹）被用于缩小拮抗剂的选择范围，以进一步研究 5-CK 的作用机制。接下来，基于指纹分析的结果，在痛觉试验中进行了功能性拮抗剂测定。GABA 受体拮抗剂印防己毒素完全逆转了 5-CK 在冷板和尾部闪烁试验中的作用，但阿托品或格列本脲没有逆转。分子对接研究表明，5-CK 与正位结合位点结合，与观察到的印防己毒素和 GABA 的结合模式相似。这些结果表明 5-CK 具有中枢介导的镇痛作用，可能涉及 GABA 能途径的激活。
