Potent inhibition of mammalian progesterone synthesis by 2 alpha-cyanoprogesterone.
2 alpha-Cyanoprogesterone potently inhibits the conversion of [3H]pregnenolone into progesterone catalysed by bovine corpora lutea, bovine adrenal cortex and human term placenta microsomes (microsomal fractions), yielding IC50 (concentration causing 50% inhibition) values of 66 nM, 120 nM and 700 nM respectively. By contrast, it is an exceedingly poor inhibitor of the isomerization of pregn-5-ene-3,20-dione, yielding IC50 values between 50 and 70 microM. On this basis, 2 alpha-cyanoprogesterone would appear to be an extraordinarily selective inhibitor of the 3 beta-hydroxysteroid dehydrogenase. Dixon plots indicate that it is a very-tight-binding competitive inhibitor of the corpus-luteum enzyme, yielding a Ki of 15 nM. In the bovine adrenal cortex and human placenta the steroid is less potent and inhibits the dehydrogenase non-competitively with Ki values of 150 nM and 1.0 microM respectively. Thus 2 alpha-cyanoprogesterone inhibits the corpus-luteum dehydrogenase with substantial selectivity. Because of its high affinity for the ovarian enzyme, the presence of low-micromolar concentrations of 2 alpha-cyanoprogesterone can promote a complete cessation of progesterone synthesis in corpora-lutea microsomes for several hours. Since this effect is observed in the presence of saturating concentrations of pregnenolone (50 microM), it is predicted that this inhibitor may be even more potent in vivo. 2 alpha-Cyanoprogesterone displays very low affinity for the human progesterone receptor, yielding a Kd of 600 nM as against a Kd of 1.6 nM for progesterone. It is suggested that 2 alpha-cyanoprogesterone may be a selective inhibitor of ovarian progesterone synthesis and may act as an effective anti-gestational agent in vivo.
D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors; D000302:Adrenal Cortex / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D003338:Corpus Luteum / Q000378:metabolism; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011284:Pregnenolone / Q000378:metabolism; D011374:Progesterone / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000187:drug effects
D011980:Receptors, Progesterone; C045085:2-hydroxymethyleneprogesterone; D011374:Progesterone; D011284:Pregnenolone; C045077:2-cyanoprogesterone; D015096:3-Hydroxysteroid Dehydrogenases