Institute of Preclinical Sciences, Veterinary Faculty, University of Ljubljana, Gerbičeva 60, 1000 Ljubljana, Slovenia.
Int J Mol Sci. 2024 Aug 21;25(16):9049. doi: 10.3390/ijms25169049.
Cholinesterase (ChE) inhibitors are crucial therapeutic agents for the symptomatic treatment of certain chronic neurodegenerative diseases linked to functional disorders of the cholinergic system. Significant research efforts have been made to develop novel derivatives of classical ChE inhibitors and ChE inhibitors with novel scaffolds. Over the past decade, ruthenium complexes have emerged as promising novel therapeutic alternatives for the treatment of neurodegenerative diseases. Our research group has investigated a number of newly synthesized organoruthenium(II) complexes for their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Three complexes (C1a, C1-C, and C1) inhibit ChE in a pharmacologically relevant range. C1a reversibly inhibits AChE and BChE without undesirable peripheral effects, making it a promising candidate for the treatment of Alzheimer's disease. C1-Cl complex reversibly and competitively inhibits ChEs, particularly AChE. It inhibits nerve-evoked skeletal muscle twitch and tetanic contraction in a concentration-dependent manner with no effect on directly elicited twitch and tetanic contraction and is promising for further preclinical studies as a competitive neuromuscular blocking agent. C1 is a selective, competitive, and reversible inhibitor of BChE that inhibits horse serum BChE (hsBChE) without significant effect on the peripheral neuromuscular system and is a highly species-specific inhibitor of hsBChE that could serve as a species-specific drug target. This research contributes to the expanding knowledge of ChE inhibitors based on ruthenium complexes and highlights their potential as promising therapeutic candidates for chronic neurodegenerative diseases.
胆碱酯酶 (ChE) 抑制剂是治疗某些与胆碱能系统功能障碍相关的慢性神经退行性疾病的重要治疗药物。人们已经做出了巨大的努力来开发新型的经典 ChE 抑制剂和具有新型骨架的 ChE 抑制剂的衍生物。在过去的十年中，钌配合物已成为治疗神经退行性疾病的有前途的新型治疗替代物。我们的研究小组研究了许多新合成的有机钌 (II) 配合物，以研究它们对乙酰胆碱酯酶 (AChE) 和丁酰胆碱酯酶 (BChE) 的抑制活性。三种配合物 (C1a、C1-C 和 C1) 在药理学相关范围内抑制 ChE。C1a 可逆地抑制 AChE 和 BChE，而没有不良的外周作用，使其成为治疗阿尔茨海默病的有前途的候选药物。C1-Cl 配合物可逆且竞争性地抑制 ChE，特别是 AChE。它以浓度依赖的方式抑制神经诱发的骨骼肌抽搐和强直性收缩，而对直接诱发的抽搐和强直性收缩没有影响，作为一种竞争性神经肌肉阻滞剂，有望进一步进行临床前研究。C1 是一种选择性、竞争性和可逆的 BChE 抑制剂，它抑制马血清 BChE (hsBChE)，而对周围神经肌肉系统没有显著影响，并且是 hsBChE 的高度种特异性抑制剂，可作为种特异性药物靶标。这项研究为基于钌配合物的 ChE 抑制剂的扩展知识做出了贡献，并强调了它们作为慢性神经退行性疾病有前途的治疗候选物的潜力。
