离子液体毛果芸香碱类似物作为抗青光眼候选药物,ACS Pharmacology & Translational Science

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离子液体毛果芸香碱类似物作为抗青光眼候选药物
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2022-07-08 , DOI: 10.1021/acsptsci.2c00024
Juan Wang ₁ , Boxuan Li ₂ , Jing Tang ₃ , Li Qiu ₁ , Xin Qiao ₁ , Na Xu ₁ , Hu Yang ₄

Affiliation

合成并报道了离子液体毛果芸香碱类似物 [Pilo-OEG]Cl，这是第一种离子液体抗青光眼候选药物。为了合成[Pilo-OEG]Cl，毛果芸香碱与低聚聚乙二醇氯化物、2-[2-(2-氯乙氧基)乙氧基]乙醇反应，形成具有咪唑阳离子和氯阴离子的离子液体分子。[Pilo-OEG]Cl 的化学结构被证实为¹核磁共振氢谱。根据 pH 测量和 LC-MS 分析，与毛果芸香碱 (Pilo) 和毛果芸香碱盐酸盐 (PiloHCl) 相比，[Pilo-OEG]Cl 提高了结构稳定性。[Pilo-OEG]Cl的角膜通透系数比Pilo高2倍，比PiloHCl高8倍。[Pilo-OEG]Cl 在高达 50 mM 的广泛浓度范围内对人角膜上皮细胞没有表现出明显的毒性。PiloHCl 和 [Pilo-OEG]Cl 的体内功效在血压正常的成年棕色挪威雌性大鼠中进行了测试。研究发现 [Pilo-OEG]Cl 在降低眼内压 (IOP) 方面比 PiloHCl 更有效。根据体外 ELISA 和溶血试验以及体内组织学分析，[Pilo-OEG]Cl 比 PiloHCl 更具细胞相容性。综上所述，[Pilo-OEG]Cl 具有增强的稳定性、角膜通透性、更好的降眼压功效和改善的生物相容性，使其成为抗青光眼治疗的有前途的新候选药物。将旧的抗青光眼药物转化为具有药物活性的离子液体代表了开发青光眼药物的创新方法。

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Ionic Liquid Pilocarpine Analog as an Antiglaucoma Drug Candidate

Ionic liquid pilocarpine analog [Pilo-OEG]Cl, the first-of-its-kind ionic liquid antiglaucoma drug candidate, is synthesized and reported. To synthesize [Pilo-OEG]Cl, pilocarpine was reacted with the oligo-polyethylene glycol chloride, 2-[2-(2-chloroethoxy)ethoxy] ethanol, to form an ionic liquid molecule with an imidazole cation and a chloride anion. The chemical structure of [Pilo-OEG]Cl was confirmed with ¹H NMR spectroscopy. Compared with pilocarpine (Pilo) and pilocarpine hydrochloride (PiloHCl), [Pilo-OEG]Cl has improved structural stability according to pH measurements and LC-MS analysis. The corneal permeability coefficient of [Pilo-OEG]Cl is 2-fold higher than that of Pilo and 8-fold higher than that of PiloHCl. [Pilo-OEG]Cl does not show apparent toxicity to human corneal epithelial cells over a broad range of concentrations up to 50 mM. The in vivo efficacy of PiloHCl and [Pilo-OEG]Cl was tested in normotensive adult Brown Norway female rats. [Pilo-OEG]Cl is found to be more potent than PiloHCl in lowering the intraocular pressure (IOP). [Pilo-OEG]Cl is more cytocompatible than PiloHCl based on the in vitro ELISA and hemolysis tests and in vivo histological analysis. Taken together, [Pilo-OEG]Cl has enhanced stability, corneal permeability, better IOP-lowering efficacy, and improved biocompatibility, thus making it a promising new drug candidate for antiglaucoma therapy. Transforming old antiglaucoma drugs to pharmaceutically active ionic liquids represents an innovative approach to developing glaucoma medications.

更新日期：2022-07-08

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