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散瞳作用时间太长和全身性副作用是阿托品和东莨菪碱眼科给药常伴有的两个主要问题。前文报道了东茛菪碱的苯基丙二酸类似物作为软药的成功尝试。本研究中应用了软药设计的非活性代谢物的方法,通过延长侧链苯基丙二酸部分一个亚甲基,获得了新的先导化合物(2a)。这一延伸进一步暴露了酯基,使它更易受到酯酶的攻击。假设代谢物2a有更大的极性,在体循环中也就更易被消除。2a通过与适宜的脂肪醇和脂环醇成酯活化,再季铵化以降低其中枢副作用,即得软药4a～e,因
Morale action is too long and systemic side effects are the two main problems commonly associated with ophthalmic administration of atropine and scopolamine. We previously reported the successful attempt of phenylmalonic acid analogs of scopolamine as a soft drug. In this study, we designed a novel lead compound (2a) by using a non-active metabolite designed by the Chinese Pharmacopoeia to extend the side-chain phenylmalonic acid moiety to a methylene group. This extension further exposes the ester group, making it more susceptible to esterase attack. Assuming that metabolite 2a has a greater polarity, it is also more easily abolished in the systemic circulation. 2a is activated by esterification with a suitable fatty alcohol and alicyclic alcohol, and then quaternized to reduce its central side effects, ie soft drugs 4a-e