7 alpha-methyl-19-nortestosterone, a synthetic androgen with high potency:structure-activity comparisons with other androgens

Studies of androgen receptor (AR)-mediated events in vivo are often complic ated by problems related to hormone metabolism and pharmacokinetics. Compou nds can be metabolically transformed to agents with altered potency. We hav e investigated some aspects of the structure-activity relationships of test osterone (T) and its analogs using in vivo and in vitro assays. The dose re sponse of ventral prostate (VP) and levator ani (LA) to T, dihydrotestoster one (DHT), 19-nortestosterone (19-NT), 7 alpha-methyl-19-NT (MENT), 7 alpha -cyano-19-NT (CNNT) and 7 alpha-acetylthio-19-NT (ATNT), was investigated i n 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. T here was a good correlation between bioactivity and binding affinity to AR for the 7 alpha-substituted androgens compared to T. In contrast, relative to their binding affinity to AR, the androgenic potency of DHT and 19-NT wa s lower compared to T. The reason for the lower in vivo androgenic activity of 19-NT is attributable to its enzymatic conversion to 5 alpha-reduced-19 -NT in the prostate. In the case of DHT, the lower bioactivity could be att ributed to its faster metabolic clearance rate relative to T. The correlati on was further investigated in vitro by co-transfection of rat ARcDNA expre ssion plasmid and a reporter plasmid encoding the chloramphenicol acetyl tr ansferase (CAT) gene driven by an androgen inducible promoter into CV-I cel ls. 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 transfec tion assay for the androgens. This suggests that the in vivo bioactivity of androgens could be influenced not only by binding affinity to receptors bu t also by factors such as absorption, binding to serum proteins and metabol ism. However, the high potency of MENT is primarily related to its higher a ffinity to AR. (C) 2000 Elsevier Science Ltd. All rights reserved.