Studies were undertaken to ascertain the effects of structural modification of two well-known antiestrogens (CI-628 and U-ll,100A) on their estrogenic and antiestrogenic potencies and temporal patterns of effectiveness in the immature rat uterus. Changes in the chemical structures of these antiestrogens produce compounds with markedly different affinities for the uterine estrogen receptor as measured in an in vitro cell-free cytosol system; binding affinities relative to estradiol (100%) are: CI-628, 4% CI-680, 34% 94X1127 (94X), 222% U-ll,100A (UA), 6% and U-23,469 (U-23), 0.1%. Although all five antiestrogens (daily injections of 50 μg over three days) appear equally effective in stimulating 72 h uterine weight when given alone, or in blocking the estradiol-stimulated weight increase when given with estradiol, marked differences in their potencies are noted when the effects of the compounds are monitored beyond 24 h following a single injection. The compounds CI-628, CI-680 and UA (50 μg sc in saline), which have a methylated hydroxyl group (at the site analogous to the steroid position 3), show a prolonged maintenance of elevated levels of nuclear receptor (beyond 48 h) and elevated uterine weight (until 72 h); this correlates with a prolonged period of depressed cytoplasmic receptor levels (beyond 48 h) and prolonged uterine insensitivity to estrogen (beyond 36 h as monitored by 3 h wet weight response). In contrast, a single injection of 50 μg of 94X (having a free hydroxyl group) or U-23 (with a side chain and central ring different from UA) maintained nuclear receptor levels elevated for only 12 h (94X) or 36 h (U-23) and uterine weights declined after 36-48 h; cytoplasmic receptor levels remained depressed for only 12 h (94X) or 24 h (U-23) and then returned to control levels or above by 36 h. These latter compounds likewise evoked the shortest period of uterine insensitivity to estrogen (ineffective as antagonists by 36 h). Comparative studies with these five compounds indicate that they are effective as estrogen antagonists only so long as they maintain cytoplasmic receptor levels low, and that the magnitude of the responsiveness to estradiol after antiestrogen correlates with the extent of reappearance of cytoplasmic receptor. Thus, chemical modifications of antiestrogen structure have significant effects on their temporal patterns of effectiveness as estrogens and as estrogen antagonists.
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