Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland.
Department of Toxicology and Food Protection, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland.
Molecules. 2021 May 24;26(11):3144. doi: 10.3390/molecules26113144.
C-11 is a hybrid compound derived from 2-(2,5-dioxopyrrolidin-1-yl) propanamide, with a wide spectrum of anticonvulsant activity and low neurotoxicity. The aim of this study was to determine the effects of C-11 on the protective action of various antiepileptic drugs (i.e., carbamazepine CBZ, lacosamide LCM, lamotrigine LTG, and valproate VPA) against maximal electroshock-induced seizures (MES) in mice, as well as its neuroprotective and physicochemical/pharmacokinetic properties. Results indicate that C-11 (30 mg/kg, i.p.) significantly enhanced the anticonvulsant action of LCM ( < 0.001) and VPA ( < 0.05) but not that of CBZ and LTG in the MES test. Neither C-11 (30 mg/kg) alone nor its combination with other anticonvulsant drugs (at their ED values from the MES test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength and passive avoidance tests, respectively. Pharmacokinetic characterization revealed that C-11 had no impact on total brain concentrations of LCM or VPA in mice. Qualitative analysis of neuroprotective properties of C-11, after a single administration of pilocarpine, revealed no protective effect of this substance in the tested animals. Determination of physicochemical descriptors showed that C-11 meets the drug-likeness requirements resulting from Lipinski and Veber's rules and prediction of gastrointestinal absorption and brain penetration, which is extremely important for the CNS-active compounds.
C-11 是一种源自 2-(2,5-二氧代吡咯烷-1-基)丙酰胺的混合化合物，具有广泛的抗惊厥活性和低神经毒性。本研究旨在确定 C-11 对各种抗癫痫药物（即卡马西平 CBZ、拉科酰胺 LCM、左乙拉西坦 LTG 和丙戊酸 VPA）对最大电休克诱导的惊厥（MES）的保护作用的影响，以及其神经保护作用和物理化学/药代动力学特性。结果表明，C-11（30mg/kg，ip）显著增强了 LCM（<0.001）和 VPA（<0.05）的抗惊厥作用，但对 CBZ 和 LTG 无作用在 MES 测试中。C-11（30mg/kg）单独或与其他抗癫痫药物（从 MES 测试的 ED 值）联合使用均不影响运动协调；在烟囱中分别用握力和被动回避试验测定的骨骼肌力量和长期记忆。药代动力学特征表明，C-11 对小鼠脑中 LCM 或 VPA 的总浓度没有影响。单次给予毛果芸香碱后对 C-11 神经保护特性的定性分析表明，该物质对测试动物没有保护作用。物理化学描述符的测定表明，C-11 符合 Lipinski 和 Veber 规则以及胃肠道吸收和脑渗透预测的药物相似性要求，这对中枢神经系统活性化合物极为重要。
