A possible basis for structure–function relationship of estrogens

Abstract

It is well known that a wide variety of molecules compete for binding to the estrogen receptor and act as estrogens and/or antiestrogens. These molecules such as estradiol, diethylstilbestrol, doisynolic acid, the triarylethylenes, and cyclofenyl apparently share little resemblance which could account for their interaction with a common estrogen binding site. Knowledge of the receptor binding of triarylethylene and cyclofenyl prototypes, in particular, relative to that of the other estrogens is critical for understanding their structure-function relationship. We have carried out a study on the receptor binding specificity of triarylethylene and cyclofenyl prototypes. This study has revealed that these molecular types share considerable resemblance in their receptor binding specificity and differ from estradiol and other similar molecules in some important respects. However, comparison of their substructural binding specificities reveals the possibility that the triarylethylene and estradiol prototypes may interact with at least some common regions of the estrogen binding site. Based on this reasoning the comparative receptor binding of estrogens has been rationalized on the basis of a subsite hypothesis for the estrogen binding site. According to this hypothesis, the composite estrogen binding site is composed of essentially five subsites, and that the structurally different estrogenic prototypes can interact with different set of subsites, and thus differ in their binding orientation. The essential difference in the activity profile of estradiol prototypes and the triarylethylene antiestrogens reveals the possibility of a causal relationship between the binding orientation of a ligand and its activity profile. This model for receptor site can thus serve as a working hypothesis to rationalize the structure-function relationship of estrogens.

Centchroman, a selective estrogen receptor modulator, as a contraceptive and for the management of hormone‐related clinical disorders

“…126 Pyrrolidinoethoxy side chain at p-4-phenyl position is known to contribute to receptor binding af®nity and estrogen antagonistic and anti-implantation activities of centchroman (RBA: 5.24 AE 1.45; 5) in structure and position speci®c manner. 22,30,129,130 Its removal causes a nearly tenfold decrease in RBA (0.58 AE 0.05; 7) and loss of anti-implantation activity. 30 Pyrrolidine residue in the side chain yields more active compounds than diethylamino moiety, due to involvement of hydrocarbon components in hydrophobic receptor interaction, as its replacement with a diethyl (3.22 AE 0.77; 9) or dimethyl (1.89 AE 0.82; 10) amino function causes progressive decrease in RBA.…”

“…22,30,129,130 Its removal causes a nearly tenfold decrease in RBA (0.58 AE 0.05; 7) and loss of anti-implantation activity. 30 Pyrrolidine residue in the side chain yields more active compounds than diethylamino moiety, due to involvement of hydrocarbon components in hydrophobic receptor interaction, as its replacement with a diethyl (3.22 AE 0.77; 9) or dimethyl (1.89 AE 0.82; 10) amino function causes progressive decrease in RBA. 30 Transposition of pyrrolidinoethoxy chain to ortho-(RBA: 0.78 AE 0.14; 11) or meta-(RBA: undetectable; 12) positions on 4-phenyl ring or to para-position on 3-phenyl ring (RBA: 0.14 AE 0.03; 13) causes a marked decrease or total loss of receptor af®nity.…”

“…30 Pyrrolidine residue in the side chain yields more active compounds than diethylamino moiety, due to involvement of hydrocarbon components in hydrophobic receptor interaction, as its replacement with a diethyl (3.22 AE 0.77; 9) or dimethyl (1.89 AE 0.82; 10) amino function causes progressive decrease in RBA. 30 Transposition of pyrrolidinoethoxy chain to ortho-(RBA: 0.78 AE 0.14; 11) or meta-(RBA: undetectable; 12) positions on 4-phenyl ring or to para-position on 3-phenyl ring (RBA: 0.14 AE 0.03; 13) causes a marked decrease or total loss of receptor af®nity. 28 Introduction of 3-nbutylamino-2-hydroxypropyloxy moiety (14) in place of tert-b-aminoethoxy group, characteristic of SERMs possessing contraceptive property, led to 2.5±5-fold enhancement of anti-implantation activity of centchroman, 3,4-diaryl coumarins, and chromenes, and a signi®cant increase in RBA in accordance with estrogen agonistic activity.…”

Anti-implantation effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b)pyran, a potent antiestrogenic agent in rats

“…Although these agents (tamoxifen and ormeloxifene) have low binding affinity for ER (2%-5%), their biologically active metabolites possess considerably high affinity for ER (comparable to E 2 ) (35,19). In view of the efficacy of K-1 as an antiestrogen specifically at the receptor level, it is important to emphasize its antifertility potential as compounds belonging to benzopyrans earlier have shown promise as antideciduogenic agents in rodent and primate species (36,37).…”

Expression of estrogen receptor co-regulators SRC-1, RIP140 and NCoR and their interaction with estrogen receptor in rat uterus, under the influence of ormeloxifene

“…Ormeloxifene binds to ER in a competitive manner and interferes with the ER-ERE-mediated transcription and uterine events leading to blastocyst implantation [16][17][18]. It is estrogen agonist in bone and cardiovascular system [19][20][21] while inhibits proliferation of MCF-7 human breast cancer cells [22].…”