EVIDENCE FOR THE METABOLIC-ACTIVATION OF NON-STEROIDAL ANTIOESTROGENS - A STUDY OF STRUCTURE-ACTIVITY-RELATIONSHIPS
EVIDENCE FOR THE METABOLIC-ACTIVATION OF NON-STEROIDAL ANTIOESTROGENS - A STUDY OF STRUCTURE-ACTIVITY-RELATIONSHIPS
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DOI：
10.1111/j.1476-5381.1980.tb10912.x
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发表时间：
1980-01-01
影响因子：
7.3
通讯作者：
JORDAN, VC
中科院分区：
文献类型：
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作者：
ALLEN, KE;CLARK, ER;JORDAN, VC
1在3天未成熟大鼠子宫重量试验中，比较了他莫昔芬和单羟基他莫昔芬与对甲氧基、甲基、氟和氯他莫昔芬的雌激素和抗雌激素活性。2美雌醇的雌激素活性，美雌醇是一种雌激素受体结合亲和力低的类固醇，据信在发挥作用前脱甲基化为乙炔雌二醇，在3天未成熟大鼠子宫重量试验中测定时，其效力低于乙炔雌二醇。同样，帕拉甲氧基他莫昔芬在雌激素和抗雌激素试验中的活性低于单羟基他莫昔芬。3在他莫昔芬中引入对甲氧基基团不影响雌激素或抗雌激素活性。4在3 d未成熟大鼠子宫重量试验中，与苯甲酸雌二醇相比，所有他莫昔芬衍生物均为部分雌激素激动剂。所有供试化合物均以剂量相关方式抑制苯甲酸雌二醇（0.16 μg/天）的促子宫活性。效力顺序为：单羟基他莫昔芬>他莫昔芬>对甲氧基他莫昔芬>对氟对氯对甲基他莫昔芬。5他莫昔芬与其对甲基的活性大致相等，对氟和对氯衍生物在体外抑制[3 H]-雌二醇与大鼠子宫雌激素受体结合的能力。6他莫昔芬在阴道内给予雌二醇后抑制卵巢切除大鼠阴道角化的能力方面与其对甲基和对氟衍生物大致相同（3.2 ng总剂量）。7由于他莫昔芬体内作为部分雌激素激动剂和拮抗剂比不能代谢羟基化为单羟基他莫昔芬的对位取代的氟、氯和甲基衍生物更有活性，而在阴道角化试验中局部应用化合物的抗雌激素活性与它们抑制[3 H]- 雌二醇-17 β在体外与雌激素受体结合，这表明在低剂量下;即在部分激动剂剂量反应曲线的范围内，他莫昔芬的生物活性是母体化合物及其代谢物活性的净结果。8结果表明，非甾体抗雌激素的代谢活化仅这是一个优点，而不是抗雌激素活性的要求。
1The oestrogenic and antioestrogenic activities of tamoxifen and monohydroxytamoxifen have been compared with those ofpara‐methoxy, ‐methyl, ‐fluoro, and ‐chloro tamoxifen in the 3 day immature rat uterine weight test.2The oestrogenic activity of mestranol, a steroid with low oestrogen receptor binding affinity which is believed to be demethylated to ethinyl oestradiol before exerting its effects, was less potent than ethinyl oestradiol when assayed in the 3 day immature rat uterine weight test. Similarly,para‐methoxytamoxifen was less active than monohydroxytamoxifen in oestrogenic and antioestrogenic tests.3The introduction of apara‐methoxy group into tamoxifen did not affect oestrogenic or antioestrogenic activity.4All the derivatives of tamoxifen were partial oestrogen agonists when compared with oestradiol benzoate in the 3 d immature rat uterine weight test. All test compounds inhibited the uterotrophic activity of oestradiol benzoate (0.16 μg daily) in a dose‐related manner. The order of potency was: monohydroxytamoxifen > tamoxifen ≡ methoxytamoxifen >p‐fluoro ≡p‐chloro ≡p‐methyltamoxifen.5Tamoxifen was approximately equiactive with itsp‐methyl,p‐fluoro andp‐chloro derivatives in the ability to inhibit [3H]‐oestradiol binding to rat uterine oestrogen receptorsin vitro.6Tamoxifen was approximately equiactive with itsp‐methyl andp‐fluoro derivatives in the ability to inhibit vaginal cornification of ovariectomized rats upon intravaginal administration with oestradiol (3.2 ng total dose).7Since tamoxifenin vivowas more active as a partial oestrogen agonist and antagonist than theparasubstituted fluoro, chloro and methyl derivatives that cannot undergo metabolic hydroxylation to monohydroxytamoxifen, whereas the antioestrogenic activity of the compounds upon local application in the vaginal cornification test was equivalent as was their ability to inhibit [3H]‐oestradiol‐17 β binding to the oestrogen receptorin vitro, it is suggested that at low doses; i.e. over the range of the partial agonist dose‐response curve, the biological activity of tamoxifen is the net result of the activities of the parent compound and its metabolites.8The results demonstrate that metabolic activation of non‐steroidal antioestrogens is only an advantage and not a requirement for antioestrogenic activity.