北甲甲酮、7 -甲基北甲甲酮及其衍生物的激素性质。
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Schoonen WG, Deckers GH, de Gooijer ME, de Ries R, Kloosterboer HJ
北甲甲酮、7 -甲基北甲甲酮及其衍生物的激素性质。
中国生物化学杂志，2000年11月15日;32(4):426 - 426。doi: 10.1016 / s0960 - 0760(00) 00125 - 4。
- PubMed ID
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11162927 (PubMed视图］
- 摘要
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北甲甾酮(NET)是一种促孕化合物，具有非常弱的雄激素和雌激素作用。这些低雄激素和雌激素活性可能是由于NET本身或由NET的代谢物引起的。为了提高NET的生物活性，研究了7 -甲基取代对NET生物活性的影响。因此，本研究有两个目的:一是比较NET和7 α -甲基NET (MeNET)的生物活性，二是NET和MeNET暂定代谢产物的生物活性。代谢物由位于碳4 - 5双键(Delta(4))或5 -氢原子旁边的3-酮-、3- α -或3-羟基组成。7 -甲基取代是特别有趣的，因为它阻止了5 -甲基的还原。通过孕激素(PR)、雄激素(AR)、雌激素(ER)和糖皮质激素(GR)受体的体外结合、转激活和增殖试验，以及体内孕激素McPhail、Hershberger、雌激素Allen-Doisy试验和雌激素和孕激素联合排卵抑制试验，评价NET、MeNET及其潜在代谢物的生物学活性。NET是一种化合物，其PR结合和转激活活性比参考化合物Org 2058(100%)弱5 - 8倍，比孕酮强2倍。NET对AR (DHT=100%)的结合活性和转激活活性分别为3.2和1.1%，对ER无(E2=100%)和GR < 1% (DEX=100%)的结合活性和转激活活性。与NET相比，MeNET的促孕活性低1.5- 2倍，雄激素活性高10 - 20倍，而它对ER和GR没有活性。与NET相比，5alpha-NET的相对结合亲和力对PR低7倍，对AR高1.5倍，而在转激活试验中，5alpha-NET对所有测试受体的活性水平均低于1%。 3beta-Hydroxy-(5alpha-reduced)-metabolites showed clear ER binding and transactivation activities, while 3alpha-hydroxy-(5alpha-reduced)-metabolites did hardly possess these characteristics. These hydroxy metabolites did not bind or activate other receptors. Substitution of 7alpha-methyl to NET metabolites led to similar characteristics, but with higher activities for AR and ER and weaker activity for PR. The outcome of in vivo tests showed a remarkable effect for MeNET. Progestagenic activity in rabbits appeared for NET equipotent to or eight-fold higher than for MeNET, after subcutaneous or oral treatment, respectively. On the other hand, MeNET showed in rats a ten-fold higher androgenicity and eight-fold higher estrogenicity than NET. Ovulation inhibition was induced at very low oral or subcutaneous dose levels, being 120- or ten-fold lower than for NET, respectively. The estrogenicity can also be induced by 3alpha- or 3beta-hydroxy metabolites of MeNET, which are 15 or even more than 40-fold stronger than those of NET, respectively. In conclusion, after the introduction of a 7alpha-methyl substituent to NET an increased estrogenicity and androgenicity and a reduced progestagenic activity was found. The in vivo estrogenicity is mainly due to 3beta-hydroxy-MeNET and to a lesser extent to 3alpha-hydroxy-MeNET, while the androgenicity and progestagenicity are most likely caused by MeNET itself. Since the 7alpha-methyl substituent inhibits 5alpha-reductase, 5alpha-reduced MeNET metabolites can be excluded from biological activities. As MeNET is a very effective ovulation inhibitor, due to its mixed progestagenic and estrogenic profile, a further reduction of androgenicity of MeNET may yield new contraceptives with an attractive profile for contraception.
引用本文的药物库数据
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- 药物酶
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药物 酶 种类 生物 药理作用 行动 Norethisterone 3 -羟基甾体脱氢酶/Delta 5- >4-异构酶 蛋白质 人类 未知的底物细节 Norethisterone 3-oxo-5- α -甾体4-脱氢酶(蛋白质组) 蛋白质组 人类 未知的底物细节 Norethisterone 3-oxo-5-beta-steroid 4-dehydrogenase 蛋白质 人类 未知的底物细节 Norethisterone 醛酮还原酶家族1成员C4 蛋白质 人类 未知的底物细节 - 药物反应
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反应 细节 细节
