7α-methyl-19-nortestosterone, a synthetic androgen with high potency: Structure-activity comparisons with other androgens
Kumar,Narender; Crozat,Anne; Li,F.; Catterall,James F.; Bardin,C.Wayne; Sundaram,Kalyan
Journal of Steroid Biochemistry and Molecular Biology 71(5-6): 213-222
Publication date: 1999
Studies of androgen receptor (AR)-mediated events in vivo are often complicated by problems related to hormone metabolism and pharmacokinetics. Compounds can be metabolically transformed to agents with altered potency. We have investigated some aspects of the structure-activity relationships of testosterone (T) and its analogs using in vivo and in vitro assays. The dose response of ventral prostate (VP) and levator ani (LA) to T, dihydrotestosterone (DHT), 19-nortestosterone (19-NT), 7a-methyl-19-NT (MENT), 7a-cyano-19-NT (CNNT) and 7a-acetylthio-19-NT (ATNT), was investigated in castrated rats. The most potent androgenic steroid (VP response) was MENT followed by T, DHT, 19-NT, ATNT, and CNNT. On the other hand, the order of anabolic potency (LA response) was MENT>19-NT>T>DHT>ATNT>CNNT. There was a good correlation between bioactivity and binding affinity to AR for the 7a-substituted androgens compared to T. In contrast, relative to their binding affinity to AR, the androgenic potency of DHT and 19-NT was lower compared to T. The reason for the lower in vivo androgenic activity of 19-NT is attributable to its enzymatic conversion to 5a-reduced-19-NT in the prostate. In the case of DHT, the lower bioactivity could be attributed to its faster metabolic clearance rate relative to T. The correlation was further investigated in vitro by co-transfection of rat ARcDNA expression plasmid and a reporter plasmid encoding the chloramphenicol acetyl transferase (CAT) gene driven by an androgen inducible promoter into CV-1 cells. All the androgens led to a dose-dependent increase in the CAT activity. MENT was found to be the most potent followed by DHT, 19-NT, T, and CNNT. The specificity of the androgenic response was confirmed by its inhibition with hydroxyflutamide, an antiandrogen. Thus, there was a good correlation between binding affinity and in vitro bioactivity in the transient transfection assay for the androgens. This suggests that the in vivo bioactivity of androgens could be influenced not only by binding affinity to receptors but also by factors such as absorption, binding to serum proteins and metabolism. However, the high potency of MENT is primarily related to its higher affinity to AR.