Anabolic activity unsaturation

Comparison of 17a-methyltestosterone (S-2), 17a-methyl-5a-dihydro-testosterone (D-2), and 17o -methyl-d -testosterone (S-107) revealed that the presence of the double bond in the 4,5-position enhanced the anabolic activity and did not alter the androgenic activity, according to Beyler et al. [124]. Additional unsaturation lowered both anabolic and androgenic activities, but decreased the anabolic activity to a lesser degree. 

Extension of unsaturation also increases the androgenic and anabolic activities in some cases. The heteroannular dienone, l3/3,17a-diethyl-17/3-hydroxygona-4,9(10j-dien-3-one (N-98) and several heteroannular trienones, 7a,17a-dimethyl-17/3-hydroxyestra-4,9(10),l l-trien-3-one (N-102), 17j8-acetoxyestra-4,9(10),l l-trien-3-one (N-103), 17/3-methoxy-methyloxyestra-4,9,1 l-trien-3-one (N-104), 17/3-hydroxyestra-4,9,l 1-trien-3-one-17- -decanoate (N-105), and 17/3-hydroxyestra-4,9,l 1-trien-3-one 17-carbobenzoxyate (N-106) all exhibit very large increases in both androgenic and anabolic activities. The ratio is not favorable. 

The 3-substituted A -derivatives have already been considered under 3-substitution. Introduction of 5,6-unsaturation into the saturated 5a-androstan-17)3-ol causes decreases in both potencies the assistance provided by the electron cloud of this substitution at this position must not be important. 17j8-Hydroxyandrost-5-ene (A-49) and 17a-methyl-17j8-hydroxyandrost-5-ene (A-59) both show decreased androgenic and anabolic potencies and an unfavorable ratio compared to the parent saturated compound. Additional unsaturation between carbons 3 and 4 will further decrease the activities. 17/3-Hydroxyandrost-3,5-diene (A-150) and 17a-methyl-17j8-hydroxyandrost-3,5-diene (A-48) show decreased activities compared to the A -analogs, A-49 and A-59, or to 17/3-hydroxyandrost-3-ene (A-3). 

Comparison of 17a-methyl-17)8-hydroxy-5a -androstano[3,2-r] pyrazole (D-l 1), 17a-methyl-17)8-hydroxyandrost-4-eno[3,2-c]pyrazole (A-157), and 17a-methyl-17/3-hydroxyandrost-4,6-dieno[3,2-c]pyrazole (A-168) showed that as the degree of unsaturation is increased there is a corresponding decrease in the anabolic and androgenic activities, with the last compound (A-168) having complete loss of these activities. It was suggested [124] that the anabolic and androgenic properties of this compound were lost due to the flattening imposed by the steroidal diene system. It was also found that introduction of an additional double bond between carbons 6 and 7 in 4-chlorotestosterone acetate (S-I48) results in the complete loss of activity (compare with S-146). 

The facts that inversion of configuration at C-9 is possible without abolishing the activity and that removal of the hydrogen (introduction of unsaturation between carbons 9 and 10) sometimes decreases (N-96) the androgenic and anabolic potencies and in many cases increases both potencies, point to the lack of importance of attachment to the receptor at carbon-9. Substitution of the 9-hydrogen by bulkier substituents usually decreases the activity but in the case of fluorine it increases it (S-19 and S-25). Removal of the 9-hydrogen and the simultaneous introduction of unsaturation between carbons 11 and 12 greatly enhances the activities. These facts also point to the uninvolvement of C-9 in the attachment to the receptor site. 

The balance between the anabolism and catabolism of HA is maintained by the inhibitors of hyaluronidases. Heparin is a known and well-characterized inhibitor of hyaluronidase [132]. Chitosan inhibits HA degradation by venom and bovine testicular hyaluronidases [133]. Cis-unsaturated fatty acids can also inhibit the hyaluronidase activity [134]. Certain anti-inflammatory drugs including saly-cylates, indomethacin and dexamethasone are also known to exert anti-hyaluronidase activity [133, 135]. Ascorbic acid [136], as well as plant derived bioactive compounds, such as flavonoids, tannins, pectins, curcumins, cou-marins, gylcyrrhizin are used to block hyaluronidase activity [100]. 

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