Assignment of Anabolic-Androgenic and Antiandrogenic Properties to Some Chlorine-Substituted Steroids on the Basis of Their Binding Characteristics to the Androgen Receptor of the Rat Seminal Vesicle¹)

Summary

In this study we investigated the affinity of several 4-chlorinated and 1-ene derivatives of 17α-methyltestosterone (MT) and 17α-methyl-5α-dihydrotestosterone (MDHT) to the androgen receptor, and, additionally, the effect of a few MT-derived steroids on the activity of the 5α-reductase enzyme present in the rat seminal vesicle. From our results we conclude, that 1. Δ1 or/and Δ4 double bonds in ring A counteract the inhibition of receptor-binding caused by chlorine-substitution at C4; 2. the dissociation of myotropic and androgenic effects [=M/A dissociation] of 4-chloro-MT (as compared to MT) is due to its inactivation by 5α-reductase in androgen target organs and/or to the inhibition of the conversion of endogenous testosterone to DHT; 3. the M/A dissociation of 1-ene-MT and 4-chloro-l-ene-MT may be explained by their inability to be activated by 5α-reductase; 4. for the same reason, M/A dissociation can be assigned to the effects of 4α-chloro-l-ene-DHT.

We determined the short-term and long-term competition of cyproterone acetate and chlormadinone acetate with [³H]DHT for receptor binding at 0^°C and showed, that the complexes formed by these antiandrogens with the androgen receptor have equally reduced stabilities compared to the DHT-receptor complex.

Key words

Chloro-steroids - Androgen receptor affinity - 5α-reductase - Seminal vesicle