It has previously been shown that spironolactone possesses antiandrogenic activity in the rat and interacts with rat prostate 5α-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 5a-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 ± 1% (mean ± SE), respectively, of the Ka for spironolactone]. These findings would predict this analog to have reduced antiandrogenicity at equivalent therapeutic doses.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Clinical Biochemistry
- Biochemistry, medical