Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland.
Molecules. 2021 Mar 12;26(6):1564. doi: 10.3390/molecules26061564.
The new series of 3-(2-chlorophenyl)- and 3-(3-chlorophenyl)-pyrrolidine-2,5-dione-acetamide derivatives as potential anticonvulsant and analgesic agents was synthesized. The compounds obtained were evaluated in the following acute models of epilepsy: maximal electroshock (MES), psychomotor (6 Hz, 32 mA), and subcutaneous pentylenetetrazole (PTZ) seizure tests. The most active substance-3-(2-chlorophenyl)-1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-pyrrolidine-2,5-dione () showed more beneficial ED and protective index values than the reference drug-valproic acid (68.30 mg/kg vs. 252.74 mg/kg in the MES test and 28.20 mg/kg vs. 130.64 mg/kg in the 6 Hz (32 mA) test, respectively). Since anticonvulsant drugs are often effective in neuropathic pain management, the antinociceptive activity for two the promising compounds-namely, and -was also investigated in the formalin model of tonic pain. Additionally, for the aforementioned compounds, the affinity for the voltage-gated sodium and calcium channels, as well as GABA and TRPV1 receptors, was determined. As a result, the most probable molecular mechanism of action for the most active compound relies on interaction with neuronal voltage-sensitive sodium (site 2) and L-type calcium channels. Compounds and were also tested for their neurotoxic and hepatotoxic properties and showed no significant cytotoxic effect.
新的 3-(2-氯苯基)-和 3-(3-氯苯基)-吡咯烷-2,5-二酮-乙酰胺衍生物系列作为潜在的抗惊厥和镇痛剂被合成。所得到的化合物在以下几种急性癫痫模型中进行了评估：最大电休克（MES）、运动（6 Hz，32 mA）和皮下戊四氮（PTZ）惊厥测试。最活跃的物质 3-(2-氯苯基)-1-{2-[4-(4-氟苯基)哌嗪-1-基]-2-氧代乙基}-吡咯烷-2,5-二酮（）在 MES 测试中，其 ED 和保护指数值比参考药物丙戊酸（68.30 mg/kg 比 252.74 mg/kg）更有利，在 6 Hz（32 mA）测试中，其 ED 和保护指数值比参考药物丙戊酸（28.20 mg/kg 比 130.64 mg/kg）更有利。由于抗惊厥药物通常在神经病理性疼痛管理中有效，因此还研究了两种有前途的化合物——和——在福尔马林强直痛模型中的镇痛活性。此外，还测定了上述两种化合物对电压门控钠和钙通道以及 GABA 和 TRPV1 受体的亲和力。结果表明，最活跃的化合物的可能分子作用机制依赖于与神经元电压敏感的钠（部位 2）和 L 型钙通道的相互作用。还测试了化合物和它们的神经毒性和肝毒性，没有显示出明显的细胞毒性作用。
