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Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands.

Ng HW, Perkins R, Tong W, Hong H - Int J Environ Res Public Health (2014)

Bottom Line: The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs.Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes.Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed.

View Article: PubMed Central - PubMed

Affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA. Huiwen.Ng@fda.hhs.gov.

ABSTRACT
The estrogen receptors (ERs) are a group of versatile receptors. They regulate an enormity of processes starting in early life and continuing through sexual reproduction, development, and end of life. This review provides a background and structural perspective for the ERs as part of the nuclear receptor superfamily and discusses the ER versatility and promiscuity. The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs. Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes. Even when interacting with endogenous hormones, ER actions can have adverse effects in disease progression. Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed. The intent of this review is to complement the large body of literature with emphasis on most recent developments in selective ER ligands.

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Related in: MedlinePlus

The non-steroidal AC-131 was used as the template in a SAR study to produce analogues such as compound 13 that showed ERβ selectivity. The feature that led to the ERβ selectivity for 8β-VE was repulsion from unfavorable interaction with M336 in ERβ, and for SERM-β1 was favorable hydrophobic contact with I373 in ERβ).
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ijerph-11-08709-f010: The non-steroidal AC-131 was used as the template in a SAR study to produce analogues such as compound 13 that showed ERβ selectivity. The feature that led to the ERβ selectivity for 8β-VE was repulsion from unfavorable interaction with M336 in ERβ, and for SERM-β1 was favorable hydrophobic contact with I373 in ERβ).

Mentions: Sunden et al. [124] used compound AC-131 (Figure 10) as a template for enantio-selective SAR studies to generate the dihydrobenzofurans as ERβ agonists. The analogues generated were found to be highly potent (with EC50 as low as < 1 nM). While binding assays were not conducted, reporter gene assays showed 1,000-fold selectivity for ERβ over ERα with good potency of ~10 nM for compound 13 (trans-10-SS). A receptor selection and amplification technology (R-SAT) assay performed on this compound also demonstrated ERβ selectivity i.e., pEC50 of 7.6 for ERβ and <5 for ERα. SAR indicated that a larger and flexible ring could potentially increase selectivity and activity. In particular, compound 13 with the larger cycloheptyl ring (as compared to cyclohexyl rings) achieved its remarkable ERβ selectivity in a manner similar to potent ERβ agonists, SERM-β1 [128] and 8β-VE2 (Figure 10) [129]. Docking and protein crystal structure studies of compound 10 and similar compounds, as well as SERM-β1, indicate that the benzofuran moiety faced I373 (as with the butyl group in SERM-β1), which led to favorable non-polar interactions, while the cycloheptyl group which was close to M336, led to steric repulsion (as with the vinyl group in 8β-VE2).


Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands.

Ng HW, Perkins R, Tong W, Hong H - Int J Environ Res Public Health (2014)

The non-steroidal AC-131 was used as the template in a SAR study to produce analogues such as compound 13 that showed ERβ selectivity. The feature that led to the ERβ selectivity for 8β-VE was repulsion from unfavorable interaction with M336 in ERβ, and for SERM-β1 was favorable hydrophobic contact with I373 in ERβ).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4198987&req=5

ijerph-11-08709-f010: The non-steroidal AC-131 was used as the template in a SAR study to produce analogues such as compound 13 that showed ERβ selectivity. The feature that led to the ERβ selectivity for 8β-VE was repulsion from unfavorable interaction with M336 in ERβ, and for SERM-β1 was favorable hydrophobic contact with I373 in ERβ).
Mentions: Sunden et al. [124] used compound AC-131 (Figure 10) as a template for enantio-selective SAR studies to generate the dihydrobenzofurans as ERβ agonists. The analogues generated were found to be highly potent (with EC50 as low as < 1 nM). While binding assays were not conducted, reporter gene assays showed 1,000-fold selectivity for ERβ over ERα with good potency of ~10 nM for compound 13 (trans-10-SS). A receptor selection and amplification technology (R-SAT) assay performed on this compound also demonstrated ERβ selectivity i.e., pEC50 of 7.6 for ERβ and <5 for ERα. SAR indicated that a larger and flexible ring could potentially increase selectivity and activity. In particular, compound 13 with the larger cycloheptyl ring (as compared to cyclohexyl rings) achieved its remarkable ERβ selectivity in a manner similar to potent ERβ agonists, SERM-β1 [128] and 8β-VE2 (Figure 10) [129]. Docking and protein crystal structure studies of compound 10 and similar compounds, as well as SERM-β1, indicate that the benzofuran moiety faced I373 (as with the butyl group in SERM-β1), which led to favorable non-polar interactions, while the cycloheptyl group which was close to M336, led to steric repulsion (as with the vinyl group in 8β-VE2).

Bottom Line: The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs.Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes.Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed.

View Article: PubMed Central - PubMed

Affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, USA. Huiwen.Ng@fda.hhs.gov.

ABSTRACT
The estrogen receptors (ERs) are a group of versatile receptors. They regulate an enormity of processes starting in early life and continuing through sexual reproduction, development, and end of life. This review provides a background and structural perspective for the ERs as part of the nuclear receptor superfamily and discusses the ER versatility and promiscuity. The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs. Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes. Even when interacting with endogenous hormones, ER actions can have adverse effects in disease progression. Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed. The intent of this review is to complement the large body of literature with emphasis on most recent developments in selective ER ligands.

Show MeSH
Related in: MedlinePlus