Obniska Jolanta, Sałat Kinga, Librowski Tadeusz, Kamiński Krzysztof, Lipkowska Anna, Wiklik Beata, Rybka Sabina, Rapacz Anna
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
Department of Pharmacodynamics, Chair of Pharmacodynamics, Jagiellonian University Medical College, Kraków, Poland.
Pharmacol Rep. 2015 Feb;67(1):63-8. doi: 10.1016/j.pharep.2014.08.002. Epub 2014 Aug 20.
Accumulated data indicate that anticonvulsants possess antinociceptive properties in rodent pain models. In view of the anticonvulsant activity demonstrated previously among N-Mannich bases derived from 3-mono- (1-6) and 3,3-disubstituted pyrrolidine-2,5-diones (7-14) their analgesic activity has been investigated in the formalin model of tonic pain in mice.
The compounds 1-14 were tested at doses equal to the respective ED50 values obtained earlier in the MES test. 0.5% formalin solution was given as intraplantar injections into the hind paw of the mouse and the duration of the nocifensive response was counted in drug-treated and vehicle-treated animals in the acute and the late phases of the test.
A significant antinociceptive activity was observed for majority of the compounds. In the first phase of the test all the active compounds, except for 9-11, reduced the duration of the licking response up to 88% (compounds 2 and 6; p<0.001). In the late phase the 1-3, 5, 6, 9 and 14 were the most effective agents and their analgesic activities ranged from 92 to 100%.
The results of the research indicate that some of the investigated compounds reduced effectively either both phases of the test or were able to attenuate pain during only the acute or late phase of the formalin test. These properties, which are particularly strong in case of the compounds 1-3, 5, 6, 9 and 14, might be relevant for the development of novel analgesic-active compounds and their possible use in neuropathic pain syndromes.
积累的数据表明，抗惊厥药在啮齿动物疼痛模型中具有抗伤害感受特性。鉴于先前在源自3-单取代（1-6）和3,3-二取代吡咯烷-2,5-二酮（7-14）的N-曼尼希碱中证明的抗惊厥活性，已在小鼠强直性疼痛的福尔马林模型中研究了它们的镇痛活性。
以等于先前在最大电休克（MES）试验中获得的各自半数有效剂量（ED50）的值对化合物1-14进行测试。将0.5%福尔马林溶液经足底注射到小鼠后爪中，并在测试的急性和晚期阶段对药物处理组和赋形剂处理组动物的伤害性反应持续时间进行计数。
观察到大多数化合物具有显著的抗伤害感受活性。在测试的第一阶段，除9-11外，所有活性化合物均将舔舐反应的持续时间缩短了高达88%（化合物2和6；p<0.001）。在晚期阶段，1-3、5、6、9和14是最有效的药物，其镇痛活性范围为92%至100%。
研究结果表明，一些被研究的化合物在福尔马林测试中有效地降低了两个阶段的疼痛，或者仅在急性或晚期阶段减轻了疼痛。这些特性在化合物1-3、5、6、9和14的情况下尤为突出，可能与新型镇痛活性化合物的开发及其在神经性疼痛综合征中的可能应用有关。
