Androgen receptor binding and androgenicity of methylated 4-ene-3-ketosteroids having no 17-hydroxy group

Abstract

Certain 7α-methyl-19-norandrostenes and steroids that have no hydroxy group on ring D can compete with 5α-[ 3H]-dihydrotestosterone. (DHT) for binding to the androgen receptor protein of rat ventral prostate. The relative receptor binding affinities and competition indices (in parentheses) for these steroids are in decreasing order: 7α-methyl-19-nortestosterone (2.65) > DHT (1.00) > 7α-methyl-19-norandrost-4-ene-3-17-dione (0.16) > 7α,17,17-trimethylgona-4,13-dien-3-one (TMGD) (0.08) > 4-androstenedione (0.03) > 17-deoxy-5α-dihydrotestosterone (0.00). The results confirm our earlier finding that the 7α-methyl-19-nor-4-ene-3-keto structure can contribute substantially to the high receptor binding activity of androsta(e)nes. Thus, TMGD, which does not have an oxygen function on ring D has a surprisingly high receptor binding affinity. TMGD also competed with [ 3H]-DHT for nuclear binding if the steroids were incubated with the prostate homogenate; such competition was not observed when the incubation was carried out with minced prostate. The results suggest that, in the intact cell, TMGD does not readily penetrate into the intracellular site to interact with the receptor protein. It is apparently for this reason that TMGD was found to be neither androgenic nor antiandrogenic at doses from 5 to 30 μg per 50 g rat.