Cutler G B, Sauer M A, Loriaux D L
J Pharmacol Exp Ther. 1979 Apr;209(1):144-6.
The widely used mineralocorticoid antagonist spironolactone has antiandrogenic activity that may contribute to its side effects of decreased libido, impotence and gynecomastia. We have therefore sought a less antiandrogenic analog of spironolactone that may exhibit reduced endocrine side effects. The analog SC 25152 was chosen for pharmacological testing because of the previous observation that it has considerably reduced affinity for the androgen receptor of both man and rat but exhibits an affinity for the mineralocorticoid receptor similar to that of spironolactone. Bioassays in the rat show that SC 25152 has a 60% decrease in antiandrogenicity, and a 4-fold increase in antimineralocorticoid activity compared to spironolactone, resulting in an overall reduction of antiandrogenic activity to one-tenth that of spironolactone at doses giving equal antimineralocorticoid activity. These studies demonstrate that the antiandrogenic and antimineralocorticoid activities of spironolactone analogs can be dissociated and illustrates the utility of measurements of drug-receptor interaction to identify a compound with desired pharmacological properties.
广泛使用的盐皮质激素拮抗剂螺内酯具有抗雄激素活性，这可能是其导致性欲减退、阳痿和男性乳房发育等副作用的原因。因此，我们一直在寻找一种抗雄激素作用较弱的螺内酯类似物，其内分泌副作用可能会减少。选择类似物SC 25152进行药理测试，是因为之前的观察发现它对人和大鼠的雄激素受体亲和力大幅降低，但对盐皮质激素受体的亲和力与螺内酯相似。在大鼠身上进行的生物测定表明，与螺内酯相比，SC 25152的抗雄激素性降低了60%，抗盐皮质激素活性增加了4倍，在产生相同抗盐皮质激素活性的剂量下，其抗雄激素活性总体降低至螺内酯的十分之一。这些研究表明，螺内酯类似物的抗雄激素和抗盐皮质激素活性可以分离，并说明了测量药物-受体相互作用以鉴定具有所需药理特性的化合物的实用性。
