19-Nortestosterone anabolic activity

The presence of a 7a-methyl group has been found to potentiate anabolic activity. Acetylation of 19-nortestosterone affords the corresponding 17-acetate... 

Anabolic activities of testosterone, such as increases in amino acid incorporation into protein and in RNA polymerase activity, have been demonstrated in skeletal muscle. Apart from the direct anabolic effects in specific tissue, androgens antagonize the protein catabolic action of glucocorticoids. The androgen compounds with the greatest ratio of protein anabolic effects to virilizing effects are the 19-nortestosterone derivatives. Compounds that are used clinically (Table 63.3) include nandrolone phenpropionate (Durabolin), nandrolone decanoate... 

Nortestosterone. 1 -Methyl-A -3-desoxo-5a-dihydro 17-acetate (N-64), la-methyl 5a-dihydro (N-48), la-methyl 5a-dihydro 17-acetate (N-61), la-hydroxy 5a-dihydro 17-acetate (N-62), la,2a-methylene 5a-dihydro 17-acetate (N-63), and la-methyl-A -5a-dihydro 17-acetate (N-65) substitutions all markedly decrease the androgenic activity while the anabolic activity is decreased in a smaller degree. The anabolic-androgenic ratio becomes favorable. 

A -Nortestosterone (N-95), 17a-methyl-A -nortestosterone (N-96) subcutaneously, and 17a-ethyl-A -nortestosterone (N-97) all exhibit greatly decreased androgenic activities while the anabolic activities are increased. I7a-Methyl-A -nortestosterone (N-96) orally shows increased androgenic and anabolic activities. The anabolic-androgenic ratio is very favorable in all cases. 

Nortestosterone. The I lj8-hydroxy 17a-methyl (N-66) derivative compared to 17a-methylnortestosterone (N-4) and the 1 lj8-hydroxy 17a-ethyl (N-67) derivative compared to 17a-ethylnortestosterone (N-5) show increased androgenic and anabolic activities and, in the first case, a favorable anabolic-androgenic ratio. 

Nitrogen retention evaluation [251] was as good with ]7a-ethylnor-testosterone as with testosterone propionate (subcutaneous administration) or 17a-methyltestosterone (oral administration) [250]. The calcium and phosphorus retention was also favorably affected but as a side effect, mild cholestatic jaundice was observed [256]. Also a marked increase in bromsulfalein retention was observed in humans by administration of 17a-ethylnortestosterone [257]. Other 17o -alkyl substitutions (propyl, allyl, methallyl, ethynyl) caused a decrease of the anabolic activity. A new type of derivatives of 19-nortestosterone was prepared by etherification of the 17/3-hydroxy group [12,143,258]. Among these compounds, 19-nortestosterone-17-(cyclopent-l -enyl) ether (N-81) possesses a favorable anabolic-androgenic ratio without the undesirable side effects. 

In addition to the above-described compounds, there are a few other 19-nortestosterone derivatives which display a favorable anabolic-androgenic ratio by having lower androgenic activities and maintaining the anabolic activity of the standard compound 17a-methyl-l 7j8-hydroxy-19-norandrost-2-ene (N-29), 2-cyano-17/3-acetoxy-19-norandrost-2-ene acetoxy-19-norandrost-4-eno[2,3-c ]isoxazole (N-70), 17a-methyl-17/3-hydroxy-19-norandrost-4-eno[2,3-fii]isoxazole (N-76), and I7a-methyl-17/3-hydroxy-5a-estran-3-one (N-90). 

In the 19-nortestosterone series introduction of a hydroxyl group leads to a substantial increase in the androgenic and anabolic potencies in two cases. 17a-Methyl-l l/8,17j8-dihydroxy-19-norandrost-4-en-3-one (N-66) and 17a-methyl-4,17/8-dihydroxy-19-norandrost-4-en-3-one (N-74) both display favorable anabolic-androgenic ratios. The increased activity of the 4-hydroxy derivative N-74 is particularly interesting, since 4-hydroxy substitution usually decreases the androgenic activity (see N-77). 

Nortestosterone (N-I) and 19-Nortestosterone Esters. The original results (3.33 anabolic-androgenic ratio) of Hershberger [187] were confirmed a year later [65]. In spite of the favorable ratio, nortestosterone has only short-lived activity and therefore the 17-esters are used clinically, preventing quick metabolic inactivation of the 17/8-hydroxyl group. 

This yielded an orally active agent, but it remained for Wilds and Nelson at the University of Wisconsin (40) to separate the anabolic and androgenic activities. They prepared 19-nortestosterone by a new Birch (4) reduction... 

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