Pinheiro Mariana Martins Gomes, Radulović Niko S, Miltojević Ana B, Boylan Fabio, Dias Fernandes Patrícia
Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Laboratório de Farmacologia da Dor e da Inflamação, Rio de Janeiro, Brazil.
Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.
Eur J Pharmacol. 2014 Mar 15;727:106-14. doi: 10.1016/j.ejphar.2013.12.042. Epub 2014 Jan 30.
Recently, we identified a new natural antinociceptive alkaloid ternanthranin, isopropyl N-methylanthranilate (ISOAN), from the plant species Choisya ternata Kunth (Rutaceae). In this work we concentrated on the elucidation of its mechanism of action in comparison with two other esters of this acid (methyl (MAN) and propyl (PAN)). Mice orally pre-treated with ISOAN, MAN or PAN (at 0.3, 1 and 3mg/kg) were less sensitive to chemical or thermal stimuli in different nociception models (formalin-, capsaicin- and glutamate-induced licking response, tail flick and hot plate). All compounds (1 and 3mg/kg) showed significant activity in the peripheral nociception models, as well as a dose-dependent spinal antinociceptive effect in the tail flick model. We observed that glibenclamide was able to reverse the antinociceptive effect of ISOAN in the hot plate model suggesting the involvement of K(+)ATP channels. The antinociceptive effect of MAN and PAN may be related to adrenergic, nitrergic and serotoninergic pathways. In addition, the antinociception of PAN was reverted by naloxone implying that the opioid pathway participates in its activity. The cholinergic and cannabinoid systems were found not be involved in the onset of the antinociceptive effects of any of the esters. In conclusion, isopropyl, methyl and propyl N-methylanthranilates produced significant peripheral and central antinociception at doses lower than that of morphine, the classical opioid analgesic drug, without causing toxicity.
最近，我们从植物墨西哥橘（芸香科）中鉴定出一种新的天然抗伤害性生物碱异壬酸异丙酯（ISOAN）。在这项研究中，我们着重阐明其作用机制，并与该酸的其他两种酯（甲酯（MAN）和丙酯（PAN））进行比较。用ISOAN、MAN或PAN（0.3、1和3mg/kg）口服预处理的小鼠在不同的伤害感受模型（福尔马林、辣椒素和谷氨酸诱导的舔舐反应、甩尾和热板）中对化学或热刺激的敏感性较低。所有化合物（1和3mg/kg）在周围伤害感受模型中均表现出显著活性，并且在甩尾模型中呈现剂量依赖性的脊髓抗伤害作用。我们观察到，格列本脲能够逆转ISOAN在热板模型中的抗伤害作用，提示K(+)ATP通道参与其中。MAN和PAN的抗伤害作用可能与肾上腺素能、一氧化氮能和5-羟色胺能途径有关。此外，PAN的抗伤害作用可被纳洛酮逆转，这意味着阿片类途径参与其活性。发现胆碱能和大麻素系统不参与任何一种酯的抗伤害作用的起始过程。总之，异壬酸异丙酯、甲酯和丙酯在低于经典阿片类镇痛药吗啡的剂量下产生显著的外周和中枢抗伤害作用，且无毒性。
