荷尔蒙的属性norethisterone 7 alpha-methyl-norethisterone及其衍生品。
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Schoonen工作组,德克斯公司GH,胡德艾尔我,德里斯R, Kloosterboer HJ
荷尔蒙的属性norethisterone 7 alpha-methyl-norethisterone及其衍生品。
J类固醇生物化学杂志。2000年11月15日,74(4):213 - 22所示。doi: 10.1016 / s0960 - 0760 (00) 00125 - 4。
- PubMed ID
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11162927 (在PubMed]
- 文摘
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Norethisterone(净)是一个progestagenic化合物非常弱的androgenicity和求偶性。这些低雄激素的和雌激素的活动可能归因于净净本身或代谢产物引起的。为了提高网络的生物活性,7 alpha-methyl替换的影响进行了研究。因此,本研究有两个目的:首先,比较生物活性的净和7 alpha-methyl-net (MeNET)和第二初步的生物活性代谢物的净和MeNET。代谢物包括3-keto - 3α-或3 beta-hydroxy-group位于一个双键碳4到5(δ(4))或5 alpha-hydrogen原子。7 alpha-methyl替代的特殊利益,因为它会阻止5 alpha-reduction。净的生物活性,MeNET及其潜在的代谢物被体外评估绑定,transactivation和扩散分析孕酮(PR),雄性激素(AR)、雌激素(ER)和糖皮质激素受体(GR)体内progestagenic麦克菲尔,雄性有层次感,雌激素Allen-Doisy测试和结合雌激素和progestagenic排卵抑制测试。网是一个复合五至八公关活动绑定和transactivation低于参考复合组织2058(100%)和双重强于孕激素。绑定和transactivation活动的净AR (DHT = 100%) 3.2和1.1%,分别对ER (E2 = 100%)没有和GR低于1%(敏捷= 100%)。MeNET是1.5到2倍少progestagenic和雄激素的10 - 20倍比净,虽然它不显示ER和GR活动。5的相对亲和力alpha-net低7倍的基于“增大化现实”技术公关和1.5倍高于净,而在transactivation化验5 alpha-net只是所有测试受体活性水平低于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.
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- 药物
- 药物酶
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药物 酶 类 生物 药理作用 行动 Norethisterone 3 beta-hydroxysteroid脱氢酶/δ5 - - > 4-isomerase 2型 蛋白质 人类 未知的底物细节 Norethisterone 3-oxo-5-alpha-steroid 4-dehydrogenase(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 1 Aldo-keto还原酶家族成员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
