Steroid structural requirements for high affinity binding to human sex steroid binding protein (SBP).

The sex steroid binding protein (SBP) which binds androgens circulating in the blood of man has been examined to determine the structural requirements for high affinity binding. SBP was purified partially and the ability of each of more than 150 steroids to compete with [3H]dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one) for binding to SBP was assessed. Binding was enhanced by reduction of the delta 4 double bond to 5 alpha-dihydro, addition of a methyl group at C-4 and in one case unsaturation at C-14,15. Affinity was always reduced by modifications of the C-17 beta hydroxy. Binding was also severely decreased by deletion of the keto moiety at C-3; however, relatively high affinity was retained by an alcohol or an unsubstituted pyrazole group at C-3. Certain alpha surface substitutions such as 17 alpha-ethinyl had limited effects on binding; whereas, other modifications such as 7 alpha-methyl or 17 alpha-methyl caused significant reduction in binding. Most modifications at C-2, 6, 9 or 11 also impaired affinity, and the 5 beta steroids had reduced affinity.