GEOMETRIC ISOMERS OF SUBSTITUTED TRIPHENYLETHYLENES AND ANTI-ESTROGEN ACTION
GEOMETRIC ISOMERS OF SUBSTITUTED TRIPHENYLETHYLENES AND ANTI-ESTROGEN ACTION
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DOI：
10.1210/endo-108-4-1353
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发表时间：
1981-01-01
期刊：
影响因子：
4.8
通讯作者：
ALLEN, KE
中科院分区：
文献类型：
--
作者：
JORDAN, VC;HALDEMANN, B;ALLEN, KE
他莫昔芬 ICI 47,699 [ICI 46,474 的顺式异构体]、恩氯米芬、珠氯米芬以及单羟基他莫昔芬和 CI628 [α-(p-(2-(1-吡咯烷)乙氧基)苯基)4-甲氧基-α''-硝基芪]的雌激素和抗雌激素活性在3天未成熟大鼠子宫重量测试。他莫昔芬、恩氯米芬以及单羟基他莫昔芬和 CI628 的相关几何异构体具有部分雌激素作用，并具有抗雌激素特性。 ICI 47,699 和珠氯米芬主要具有雌激素作用；然而，珠氯米芬（每日 100 μg）的抗雌激素作用是明显的，大剂量的 ICI 47,699（每日 1 或 10 mg）可完全抑制雌激素作用。与 ICI 47,699 和珠氯米芬相关的单羟基他莫昔芬和 CI628 的几何异构体具有部分雌激素性和抗雌激素特性。 ICI 47,699 的雌激素特性分为 3 种：子宫湿重升高、整个子宫 DNA 增加以及管腔上皮细胞有丝分裂活性增加。一般来说，ICI 47,699 能够通过比他莫昔芬更少的细胞质雌激素受体易位至核区室来启动 DNA 合成或有丝分裂的雌激素反应。提出了一个模型来根据受体结合的几何要求来解释抗雌激素作用。烷基氨基乙氧基侧链的空间位置至关重要。结构特异性配体-雌激素受体复合物会影响靶组织内的未来事件，以产生激动剂或拮抗剂反应。大剂量雌激素抑制完全雌激素反应的能力可能类似于激素依赖性乳腺癌治疗中药理剂量雌激素的抗肿瘤作用。
The estrogenic and antiestrogenic activities of tamoxifen ICI 47,699 [cis isomer of ICI 46,474], enclomiphene, zuclomiphene, and the geometric isomers of monohydroxytamoxifen and CI628 [.alpha.-(p-(2-(1-pyrrolidino)ethoxy)phenyl)4-methoxy-.alpha.''-nitrostilbene] were determined in the 3-day immature rat uterine weight test. Tamoxifen, enclomiphene, and the releated geometric isomers of monohydroxytamoxifen and CI628 were partially estrogenic with antiestrogenic properties. ICI 47,699 and zuclomiphene were predominantly estrogenic; however, an antiestrogen effect for zuclomiphene (100 .mu.g daily) was demonstrable and large doses of ICI 47,699 (1 or 10 mg daily) inhibited full estrogen action. The geometric isomers of monohydroxytamoxifen and CI628 related to ICI 47,699 and zuclomiphene were partially estrogenic with antiestrogenic properties. The estrogenic properties of ICI 47,699 were classified in 3 ways: elevation of uterine wet weight, increase in whole uterine DNA, and increase in the mitotic activity of luminal epithelial cells. In general, ICI 47,699 was able to initiate estrogenic responses of DNA synthesis or mitosis by translocation of fewer cytoplasmic estrogen receptors to the nuclear compartment than tamoxifen. A model is proposed to explain antiestrogen action in terms of the geometric requirements for receptor binding. The position in space of the alkylaminoethoxyside chain is of fundamental importance. A structurally specific ligand-estrogen receptor complex an influence the future events within a target tissue to produce either an agonist or an antagonist response. The ability of large doses of estrogen to inhibit a full estrogenic response may be similar to the antitumor effects of pharmacological doses of estrogen in hormone-dependent breast cancer treatment.