Cutler G B, Pita J C, Rifka S M, Menard R H, Sauer M A, Loriaux D L
J Clin Endocrinol Metab. 1978 Jul;47(1):171-5. doi: 10.1210/jcem-47-1-171.
It has previously been shown that spironolactone possesses antiandrogenic activity in the rat and interacts with rat prostate 5 alpha-dihydrotestosterone cytoplasmic receptors to block the nuclear uptake of this hormone. Current evidence suggests that this androgen receptor interaction may be an important mechanism through which spironolactone causes endocrine side effects in rat and man. We have analyzed the interactions of several spirolactone analogs with the androgen receptor of human and rat prostate and the mineralocorticoid receptor of human and rat kidney. One analog, SC 25152, was found to have considerably reduced affinity for the prostate 5 alpha-dihydrotestosterone receptor [Ka = 24 +/- 1% and 19 +/- 6% (mean +/- SE) in the human and rat, respectively, of the Ka for spironolactone] while maintaining similar affinity for the mineralocorticoid receptors of human and rat kidney [Ka = 113 +/- 37% and 86 +/- 7% (mean +/- SE), respectively, of the Ka for spironolactone]. These findings would predict this analog to have reduced antiandrogenicity at equivalent therapeutic doses.
先前的研究表明，螺内酯在大鼠体内具有抗雄激素活性，并与大鼠前列腺5α-二氢睾酮细胞质受体相互作用，以阻断该激素的核摄取。目前的证据表明，这种雄激素受体相互作用可能是螺内酯在大鼠和人类中引起内分泌副作用的重要机制。我们分析了几种螺内酯类似物与人和大鼠前列腺的雄激素受体以及人和大鼠肾脏的盐皮质激素受体之间的相互作用。发现一种类似物SC 25152对前列腺5α-二氢睾酮受体的亲和力显著降低[在人和大鼠中，其解离常数（Ka）分别为螺内酯Ka的24±1%和19±6%（平均值±标准误）]，而对人和大鼠肾脏的盐皮质激素受体保持相似的亲和力[分别为螺内酯Ka的113±37%和86±7%（平均值±标准误）]。这些发现预示该类似物在等效治疗剂量下抗雄激素性会降低。
