Sonza Daniele Regina, França Laura Von Borell du Vernay, da Silva Rita de Cássia Vilhena, Dada Anelize, Zanovello Mariana, Boeing Thaise, de Souza Priscila, Correa Rogério
Postgraduate Program in Pharmaceutical Sciences, Nucleus of Chemical-Pharmaceutical Investigations, University of Vale do Itajaí, Rua Uruguai, 458, Itajaí, Centro, 88302-901, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Aug 21. doi: 10.1007/s00210-025-04515-y.
This study aimed to evaluate the potential antispasmodic activity of 15 cyclic imides, focusing on their effects on muscarinic receptor-mediated contractions and smooth muscle relaxation in isolated rat jejunum. The compounds were tested in vitro, with rats jejunal segments pre-contracted using acetylcholine to assess relaxant activity, and during acetylcholine-induced contractions to evaluate their inhibitory effects. Structural variations among the compounds included modifications in aromatic substituents, electronegativity, and steric hindrance, which were analyzed for their impact on biological activity. The in silico analysis of overall profiles, which balanced efficacy prediction and safety, identified compounds 09, 12, 14, and possibly 01-04 as particularly promising. All tested compounds demonstrated smooth muscle relaxant activity in pre-contracted jejunal segments. Notably, compounds 01, 02, 03, 04, 06, 13, and 15 significantly inhibited acetylcholine-induced contractions. Structural analysis revealed that electronegative groups such as nitro and sulfur or bulky aromatic substituents contributed to enhanced antispasmodic effects, potentially due to increased interaction with muscarinic receptors. These findings align with literature suggesting phthalimide derivatives may modulate muscarinic receptors through allosteric or direct binding mechanisms. The results suggest that specific structural features of cyclic imides influence their antispasmodic efficacy, possibly via interactions with muscarinic receptors. These findings provide valuable insights into the design of novel therapeutic agents targeting smooth muscle disorders, emphasizing the relevance of structural optimization for enhanced pharmacological activity.
本研究旨在评估15种环状酰亚胺的潜在解痉活性，重点关注它们对毒蕈碱受体介导的收缩以及离体大鼠空肠平滑肌松弛的影响。这些化合物在体外进行测试，使用乙酰胆碱使大鼠空肠段预先收缩以评估松弛活性，并在乙酰胆碱诱导的收缩过程中评估其抑制作用。化合物之间的结构变化包括芳族取代基、电负性和空间位阻的修饰，分析了它们对生物活性的影响。对整体概况进行的计算机模拟分析在平衡疗效预测和安全性方面，确定化合物09、12、14以及可能的01 - 04特别有前景。所有测试化合物在预先收缩的空肠段中均表现出平滑肌松弛活性。值得注意的是，化合物01、02、03、04、06、13和15显著抑制乙酰胆碱诱导的收缩。结构分析表明，硝基和硫等电负性基团或庞大的芳族取代基有助于增强解痉作用，这可能是由于与毒蕈碱受体的相互作用增加所致。这些发现与文献一致，表明邻苯二甲酰亚胺衍生物可能通过变构或直接结合机制调节毒蕈碱受体。结果表明，环状酰亚胺的特定结构特征可能通过与毒蕈碱受体的相互作用影响其解痉功效。这些发现为针对平滑肌疾病的新型治疗药物设计提供了有价值的见解，强调了结构优化对增强药理活性的相关性。
