INHIBITORS OF ADRENAL P-450c11 HYDROXYLASE CHARACTERIZEDBY TWO RADIOLIGANDS AND STEROID HORMONE SECRETION

摘要

Metyrapone, a known inhibitor of 11β-hydroxylation in the adrenal cortex, usedclinically for the treatment of hypercortisolism, and etomidate, a known anesthetic drug witha potent side effect (inhibition of cortisol biosynthesis) binds with high affinity to rat adrenalmembranes. Derivatives of etomidate and of metyrapone were used as displacers of specificradioligand binding using 4-131I-iodophenyl-metomidate (131I-IMTO) and 3H-metyrapol asradioligands, respectively. Analogues of etomidate displaced both radioligands with similarpotencies, whereas derivatives of metyrapone and structurally related compounds appeared asbetter displacers of 3H-metyrapol binding. Selected correlates were also tested as inhibitors ofcortisol production measured in cell cultures by a known assay. Inhibition of cortisolproduction correlated well with the inhibitory potencies obtained by 131I-IMTO binding.