Towards the mapping of the progesterone and androgen receptors

At a time when the secondary structures of receptor proteins are being predicted from sequence data by modeling techniques, knowledge of the ligand characteristics compatible with high-affinity binding to the receptor and with efficient receptor function is indispensable. We have already compared progesterone receptor (PR) ligands in attempts to map the PR hormone-binding site. In the present study, the relative binding affinities (RBAs) of 33 steroid ligands for the cytosol androgen receptor (AR) of rat prostate, measured in a routine screening system, have been compared. Special emphasis has been given to the effects of modifications (unsaturation, methylation, substitution by halogens) that might influence AR recognition by the ring A carbonyl and also to the consequences of these changes on binding specificity. Nonsteroid antiandrogens are reputed to compete with labelled testosterone (or methyltrienolone) binding to AR. Their RBAs, however, are very low compared to those of steroid antiandrogens. It is feasible that such molecules might occupy and interact with the AR site that binds hormone. The solvent accessible surface of one Anandron conformer is highly similar to that of testosterone and this conformer can be adequately superimposed upon the structure of testosterone and of antiandrogenic Des-A steroid derivatives. The nitro group might assume the role of the ring A carbonyl of steroids; reduction of this group to an amine or a hydroxylamine completely suppresses binding. These observations, however, do not eliminate the hypothesis of interference with AR function, and consequent antiandrogenic activity, by interaction with other (adjacent) sites on AR.