Estrogen ligands

Estrogen receptors, in analogy with many other nuclear receptors, fill a double role, since they can be activated by kinase cascades independently of estrogens and of activation of the estrogen binding site by an estrogenic ligand (Fig. 3). 

From the benzoxathiins reported thus far, 117 exhibits good prospects for further development. The optimized BSC was also tested on other SERM-type ligands, including raloxifene, bazedoxifene and lasofoxifene [151]. Although some increase in ER affinity was observed, no improvement in the rat uterine profile was observed. This result indicates that the optimized side-chain from the benzoxathiins series is not easily transferable to other estrogen ligands. 

Yamamoto, Y., Wada, O., Takada, I., Yogiashi, Y., Shibata, J., Yanagisawa, J., Kitazato, K. and Kato, S. (2003) Both N- and C-terminal transactivation functions of DNA-bound ERa are blocked by a novel synthetic estrogen ligand. Biochemical and Biophysical Research Communications, 312,... 

Comparative QSAR analysis of derivatives of heterocycles as nonsteroid ligands of estrogen receptors 99CRV723. 

The concept that different ligands play an active role in ER function is apparent at the biochemical level. In addition to competitive inhibition of estrogen binding, antiestrogens induce unique conformations/stiuctures of both ERa and ER 3. This provides a structural basis for the unique biological activities displayed by the different compounds [1]. 

Sex steroid receptors are members of the steroid hormone receptor (SHR) family that ligand-dependently regulate functions of the sexual organs. Sex steroid receptors are the androgen receptor [1] (AR), the estrogen receptor a [2] and (3 [3] (ERa, ER 3), and the progesterone receptor [4] (PR). 

The yeast reporter gene assays not only assess for the interaction of the chemical with the hormone receptor, but also the ability of that receptor-chemical ligand interaction to activate the hormone DNA response element. It should be realized, however, that most of these systems have been developed with human and mammalian hormone receptors and differences in ligand potencies can occur between different animal species. A comprehensive review of in vitro assays for measuring estrogenic activity, and some of the issues of comparability, is provided by Zacharewski (1997). 

This type of analysis is now well established and has been used in many drug discovery projects over the past fifteen years. Examples include HIV protease inhibitors [13], anti-influenza drugs [14], isoform-selective ligands for the estrogen receptor [15], and many more. 

Gao H, Williams C, Labute P, Bajorath J. Binary quantitative structure-activity relationship (QSAR) analysis of estrogen receptor ligands. / Chem Inf Comput Sci 1999 39 164-8. 

IA (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors a and (3. Endocrinol. 138, 863-70. 

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