Steroid Structure and Androgenic Activity: SPECIFICITIES INVOLVED IN THE RECEPTOR BINDING AND NUCLEAR RETENTION OF VARIOUS ANDROGENS

Abstract

Abstract In rat ventral prostate the action of many natural androgens, including testosterone, appears to depend on their conversion to 5α-dihydrotestosterone that binds firmly to an androgen receptor (β protein) and is subsequently retained by cell nuclei. We have found, however, that many potent synthetic androgens can bind directly to β protein and to prostate cell nuclei without a metabolic conversion. For these studies, simple methods were devised to compare the receptor binding affinities of various androgenic steroids. These methods are especially useful if test compounds are available only in minute quantities (l1 µg). In general, the correlation between the relative competition indices of various synthetic androgens determined by these procedures and the relative androgenicities of these androgens was very good. This supports the concept that the β protein and nuclear binding of androgens play important roles in androgen actions in ventral prostates. Most of the highly active synthetic androgens that could bind to β protein were Δ4-3-ketosteroids without an angular methyl group at C-10. Since they can bind to β protein tightly, their androgen action may bypass the action of Δ4-3-ketosteroid-5α-oxidoreductase that appears to be necessary for the action of testosterone. These findings, together with molecular model building, indicate that the bulkiness and flatness of the steroid molecule play a more important role in receptor binding than the detailed electronic structure at the Δ4 bond of Ring A. For example, potent androgens with conjugated double bonds extending from Rings A and B to C (such as 2-oxa-17α-methyl-17β-hydroxy-estra-4,9,11-triene-3-one and 17α-methyl-17β-hydroxy-estra-4,9,11-triene-3-one) are indeed very flat molecules and bind to the androgen receptor firmly. Substitution of a 7α-methyl group in 17β-hydroxyestr-4-en-3-one (19-nortestosterone) or its 17α-methyl derivative enhanced the androgenic activities of the parent compounds as well as their ability to bind to β protein and to prostate cell nuclei. Thus, 7α, 17α-dimethyl-19-nortestosterone had an apparent affinity for βprotein several times higher than that of 5α-dihydrotestosterone. A tritiated form of 7α, 17α-dimethyl-19-nortestosterone was also used to show its binding to β protein and to prostate cell nuclei. The tritiated androgen appeared to be very stable to metabolic conversion in prostate tissue. Notably, it was not reduced by prostate Δ4-3-ketosteroid-5α-oxidoreductase.