Molecular Pharmacology, Vol 20, 43-51, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Stereochemical Considerations in the Binding of Nonsteroidal Estrogens to the Estrogen Receptor

¹ The Roger Adams Laboratory, School of Chemical Sciences, University of Illinois, Urbana, Illinois 61801

Derivatives of nonsteroidal estrogens, such as hexestrol, can interact with the estrogen receptor in four possible binding modes—two per enantiomer. Several side chain-functionalized hexestrol and norhexestrol derivatives have been synthesized and resolved into pure enantiomers. The absolute configuration of these enantiomers has been determined in order to assess which of the four binding modes is preferred. Binding studies with lamb uterine estrogen receptor have indicated that there is no appreciable difference in binding between enantiomers in the hexestrol series. Enantiomers in the norhexestrol series, on the other hand, do show significant differences in binding. The (—)-(2R,3S)-pentyl ester 26 binds to receptor with twice the affinity of racemic material and 14 times the affinity of the (+)-(2S,3R)-antipode. Similar though less dramatic differences are observed with methyl esters 18-20 and alcohols 30-32. It is concluded that the norhexestrols prefer one of the four possible binding modes while the hexestrols can adopt two of the four modes equally. Furthermore, comparisons between the binding affinities of corresponding hexestrol and norhexestrol derivatives suggest that the source of chiral recognition is a specific interaction between the carbonyl group in the 2R, 3S enantiomer of the norhexestrol derivatives that elevates affinity, this interaction not being attainable in the other enantiomer and in the derivatives in the hexestrol series.