软性药物——十四。美托品软性苯基琥珀酸类似物的合成与抗胆碱活性。
Soft drugs--XIV. Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine.
作者信息
Hammer R H, Gunes E, Kumar G N, Wu W M, Srinivasan V, Bodor N S
机构信息
Center for Drug Discovery, College of Pharmacy, University of Florida, Gainesville 32610.
出版信息
Bioorg Med Chem. 1993 Sep;1(3):183-7. doi: 10.1016/s0968-0896(00)82119-7.
Three soft drug analogs and a metabolite of methatropine based on phenylsuccinic structural moiety were synthesized and tested for activity. In an in vivo assay, the soft drugs were found to be two orders of magnitude less potent than methatropine while the carboxylate metabolite was found to be one order of magnitude less potent than the soft drugs. A structural isomer of compound 4a was found to be less potent. All the soft drugs tested elicited shorter durations of mydriatic action in rabbit eyes compared to atropine. The untreated eye was dilated in the atropine treated animals while no dilation occurred in the soft drug treated animals indicating facile systemic metabolism of the soft drugs to inactive moieties, possibly the carboxylate metabolite. In in vitro stability studies, the soft drugs have been found to be more hydrolytically labile than atropine. The shorter duration of mydriatic action of compound 4a coupled with increased hydrolytic lability make this a candidate for further study.
合成了三种基于苯基琥珀酸结构部分的美沙托品软药类似物及其一种代谢物，并对其活性进行了测试。在体内试验中，发现这些软药的效力比美沙托品低两个数量级，而羧酸盐代谢物的效力比软药低一个数量级。发现化合物4a的一种结构异构体效力较低。与阿托品相比，所有测试的软药在兔眼中引起的散瞳作用持续时间更短。在阿托品治疗的动物中，未治疗的眼睛会扩张，而在软药治疗的动物中未出现扩张，这表明软药易于在体内代谢为无活性部分，可能是羧酸盐代谢物。在体外稳定性研究中，发现软药比阿托品更易水解。化合物4a散瞳作用持续时间较短，且水解稳定性增加，使其成为进一步研究的候选物。
Zotero 插件