Obniska Jolanta, Rapacz Anna, Rybka Sabina, Góra Małgorzata, Żmudzki Paweł, Kamiński Krzysztof
Department of Medicinal Chemistry, Jagiellonian University Medical College, Kraków, Poland.
Faculty of Pharmacy, Department of Pharmacodynamics, Jagiellonian University Medical College, Kraków, Poland.
Arch Pharm (Weinheim). 2017 Apr;350(3-4). doi: 10.1002/ardp.201600368. Epub 2017 Mar 20.
The focused library of new amides derived from 3,3-diphenyl-2,5-dioxo-pyrrolidin-1-yl-acetic acid (2a-t) and 3,3-diphenyl-propionic acid (3a-t) as potential anticonvulsant agents was synthesized. The final products were obtained in the amidation reaction of the given carboxylic acid (2, 3) with appropriate secondary amines in the presence of carbonyldiimidazole (CDI) as a coupling reagent. The initial anticonvulsant screening was performed in mice intraperitoneally (i.p.) using the "classical" maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models, whereas the acute neurological toxicity was determined applying the rotarod test. Additionally, several compounds were studied also in the 6-Hz seizures recognized as the animal model of human pharmacoresistant epilepsy. In this series, compound 3q displayed a broad spectrum of activity across the preclinical seizure models (ED MES = 31.64 mg/kg; ED scPTZ = 75.41 mg/kg, ED 6-Hz (32 mA) = 38.15 mg/kg). Consequently, compound 3q revealed a wider spectrum of protection, higher activity or/and a better safety profile than the commonly used antiepileptic drugs such as phenytoin, ethosuximide, valproic acid, or/and levetiracetam. Notably, the in vitro studies showed that the most possible mechanism of action of 3q may be connected to the interaction with neuronal voltage-sensitive sodium channels (site 2). Other substances were active predominantly in the chemically induced seizures. The results of the current studies indicate that the presence of the pyrrolidine-2,5-dione ring is important but not indispensable for anticonvulsant activity.
合成了以3,3-二苯基-2,5-二氧代吡咯烷-1-基乙酸（2a - t）和3,3-二苯基丙酸（3a - t）为潜在抗惊厥剂的新型酰胺聚焦库。最终产物是在给定羧酸（2,3）与适当仲胺在羰基二咪唑（CDI）作为偶联剂存在下的酰胺化反应中获得的。最初的抗惊厥筛选是在小鼠中通过腹腔注射（i.p.）使用“经典”最大电休克（MES）和皮下注射戊四氮（scPTZ）癫痫发作模型进行的，而急性神经毒性则通过转棒试验确定。此外，还在被认为是人类药物抵抗性癫痫动物模型的6 - Hz癫痫发作中对几种化合物进行了研究。在该系列中，化合物3q在临床前癫痫发作模型中表现出广泛的活性（ED MES = 31.64 mg/kg；ED scPTZ = 75.41 mg/kg，ED 6 - Hz（32 mA）= 38.15 mg/kg）。因此，化合物3q显示出比常用抗癫痫药物如苯妥英、乙琥胺、丙戊酸或/和左乙拉西坦更广泛的保护谱、更高的活性或/和更好的安全性。值得注意的是，体外研究表明3q最可能的作用机制可能与与神经元电压敏感性钠通道（位点2）的相互作用有关。其他物质主要在化学诱导的癫痫发作中具有活性。当前研究结果表明，吡咯烷-2,5-二酮环的存在对于抗惊厥活性很重要，但不是必不可少的。
