aRelative binding affinities from lamb uterine cytosol at 25 °C.

Figure 35 Estradiol-based ligands with substitution at the 11 b and 17a positions.

Miller and co-workers have prepared a series of 7a-thioestratrienes represented by compounds 94 and 95 (Figure 34).118 Substitution of the steroid nucleus at 7a with a basic aryloxypiperidine side chain (94) common to many SERMs resulted in no affinity to ERa or ERb. However, 7a-substitution with an amide side chain (95) resulted in a high-affinity ligand (IC50 = 9 nmol L— 1) at ERa or ERb that was also an inhibitor of E2-stimulated growth in vitro (ERE/MCF-7) and in vivo (uterine weight gain in the immature rat). Substitution at the 6-position with carbonyl or alcohol functionality resulted in a three- to fourfold reduction in binding affinity.

Hanson and co-workers have prepared E2-based ligands in which substitution at the 11b and 17a positions has been investigated.119 In this series, the binding behavior is dependent on the substituents and geometry of the alkene as well as the nature of the 11b position (Figure 35). Optimal receptor recognition is achieved by small lipophilic groups in the 11b position, i.e., H or vinylhalo >MeO. The presence of 17a-Z-halovinyl substitution enhances RBA values relative to E2 (96-99) while 17a-E substitution has a less dramatic effect on receptor affinity.


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