The purpose of the present study was to examine the analgesic activity of six novel hybrid molecules, which demonstrated in the previous research anticonvulsant activity in the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole seizure (scPTZ) tests in mice. The antinociceptive properties were estimated in three models of pain in mice-the hot plate test, the formalin test, and in the oxaliplatin-induced neuropathy. Moreover, extended anticonvulsant studies were carried out and the antiseizure activity was investigated in the 6-Hz test. Considering drug safety evaluation, the influence of compounds on locomotor activity and contextual memory were checked. Furthermore, chosen molecules were tested in vitro for potential hepatotoxicity. To explain the probable mechanism of action, the radioligand binding assays were performed. In both phases of formalin test, analgesic activity demonstrated compounds 4, 8, and 9. These agents relieved also mechanical allodynia in oxaliplatin-induced model of neuropathic pain. At active doses, they did not influence locomotor activity of mice. Moreover, for compounds 8 and 9, no deleterious effect on memory was observed, but compound 4 might induce memory deficits. All tested compounds (4, 5, 8, 9, 15, and 16) inhibited psychomotor seizures with the ED50 values = 24.66-47.21 mg/kg. The binding studies showed that compound 4 only at the high concentrations revealed the effective binding to the neuronal sodium channels and moderately binding to the L-type calcium (verapamil site) channels and NMDA receptors. The present preclinical results proved that novel hybrid molecules demonstrate very promising anticonvulsant and analgesic activity.

中文翻译：

---

N-苄基-2-（2,5-二氧杂吡咯烷-1--1-基）丙酰胺和2-（2,5-二氧杂吡咯烷-1--1-基）丁酰胺衍生的新型杂合分子的镇痛，抗痛觉过敏和抗惊厥活性疼痛和癫痫病。

本研究的目的是检查六个新的杂合分子的镇痛活性，这在先前的研究中已在小鼠的最大电击惊厥（MES）和皮下戊四氮惊厥（scPTZ）测试中证明了其抗惊厥活性。在小鼠的三种疼痛模型（热板试验，福尔马林试验和奥沙利铂诱导的神经病）中估计了抗伤害感受的特性。此外，进行了扩展的抗惊厥研究，并在6 Hz测试中研究了抗癫痫发作的活性。考虑到药物安全性评估，检查了化合物对运动活性和情境记忆的影响。此外，在体外测试了所选分子的潜在肝毒性。为了解释可能的作用机理，进行了放射性配体结合测定。在福尔马林测试的两个阶段，镇痛活性均显示出化合物4、8和9。这些药物还减轻了奥沙利铂诱导的神经性疼痛模型中的机械性异常性疼痛。在有效剂量下，它们不影响小鼠的自发活动。而且，对于化合物8和9，未观察到对记忆的有害作用，但是化合物4可能引起记忆缺陷。所有测试的化合物（4、5、8、9、15和16）均能抑制精神运动性癫痫发作，ED50值为24.66-47.21 mg / kg。结合研究表明，只有高浓度的化合物4才能有效结合神经元钠通道，并适度结合L型钙（维拉帕米位点）通道和NMDA受体。目前的临床前结果证明，新型杂合分子表现出非常有前途的抗惊厥和止痛活性。