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.
A series of 2,3-diaryl-2H-1-benzopyrans carrying a tertiary aminoethoxy chain at the ortho, meta, or para position of 2-phenyl or an alkyl at position 4 of the pyran ring were synthesized and evaluated for their affinity for estrogen receptor (ER) and for microsomal antiestrogen specific binding site and for their uterotrophic-antiuterotrophic activities in rodents. The analogues bearing the side chain at the para position of 2-phenyl were found to be active while those substituted at the meta and ortho positions were inactive as ER ligands as well as estrogen agonists-antagonists. Among para-substituted ethers, the 2-piperidinoethoxy analogue 5 was found to be a more effective antiestrogen than the corresponding pyrrolidino, dimethylamino, and related analogues. Incorporation of a methyl or an ethyl at C4 in the pyran nucleus was found to increase receptor affinity of the prototypes. The ethyl was also found to potentiate agonist activity of the prototype while abolishing its antagonist activity. The piperidino analogue 5 was found to be a better antiestrogen than tamoxifen as well as LY-117018 in rats as well as mice. The prototypes were also found to have high affinity for the microsomal antiestrogen specific binding sites. The benzopyrans have thus emerged as a new group of potent antiestrogens.
In a study of the structure-activity relationship (SAR) of antiestrogens use has been made of certain 1,2,3-triarylbutenones, of 2-arylbenzofurans carrying aryl or aroyl substituents at C3, and of 2,3,4-triarylfurans as conformationally constrained models for triarylethylene (TAE) and triarylpropenone (TAP) prototypes. The position-specific contributions of substituents to receptor affinity and to agonist-antagonist profiles were used as aids in characterizing the relative binding orientation of the prototypes. Although most compounds were found to be weak receptor ligands and poorly active in vivo, the following conclusions could be drawn about their SAR: (i) (Z)-TAPs and TAEs interact with the receptor in an analogous manner using the trans-stilbene core, with their agonist-antagonist profiles depending on the nature of other substructures. (ii) Incorporation into the benzofuran framework introduces a stereoelectronic constraint that compromises the normal binding interactions of TAE, as well as TAP, prototypes, resulting in their poor affinities and weak biological activities. (iii) (E)-TAPs can interact with the receptor through their S-cis conformation, but such a binding mode is unlikely to account for their behavior as antagonists.
A series of 2,3-diaryl-1-benzopyran analogues substituted at position 4 of 2-phenyl with a hydroxy or pyrrolidinoethoxy residue were synthesized as models for (E)-triarylpropenones constrained in the s-trans conformation. The prototypes, belonging to five chemical series, were evaluated for their estrogen receptor affinity and for estrogen agonist-antagonist activities. The 4H-1-benzopyran-4-one, the 2,3-dihydro-4H-1-benzopyran-4-one, the 4H-1-benzopyran, and the 2,3-dihydro-1-benzopyran derivatives were found to be inactive or only marginally activate as receptor ligands or estrogen agonists-antagonists. In the 2H-1-benzopyran category the parent phenol was also inactive whereas the basic ethers 16 and 26 were modest receptor ligands while being quite active as antiestrogens. In a comparative study the benzopyran 16 was found to be more effective antiestrogen than tamoxifen while being as effective as LY-117018. The benzopyrans have thus emerged as a new class of potent antiestrogens.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.