Synthesis and structure–activity relationships of 1-benzylindane derivatives as selective agonists for estrogen receptor beta

Yonekubo, Shigeru; Fushimi, Nobuhiko; Miyagi, Takashi; Nakanishi, Osamu; Katsuno, Kenji; Ozawa, Motoyasu; Handa, Chiaki; Furuya, Noritaka; Muranaka, Hideyuki

doi:10.1016/j.bmc.2016.09.047

Cited by 15 publications

(5 citation statements)

References 35 publications

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“…The in vitro data from our previous study 27 showed that a serum C1 concentration of 10 nM–300 nM sufficiently activated ERβ with minimal effect on ERα. We have prepared sustained-release C1 pellets that maintain a serum concentration within this range in mice for 2 weeks (Fig.…”

Section: Introductionmentioning

confidence: 88%

“…C-1 was synthesized as described previously 27 . C1 pellets were developed to maintain a plasma concentration within the range (i.e.…”

Section: Methodsmentioning

confidence: 99%

“…1) 27 . C-1 has a 256-fold higher agonistic selectivity for ERβ than ERα (Tables 1 and 2) 27 . To elucidate the potential effects of ERβ activation in postmenopausal women, we investigated the impact of C-1 in OVX mice.…”

Section: Introductionmentioning

confidence: 99%

“…Detailed information can be found in ref. 27. Abbreviations : EC50 , half maximal (50%) effective concentration; hER , human estrogen receptor; RBA , relative binding activity.…”

Section: Introductionmentioning

confidence: 99%

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Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Sasayama

Sugiyama

Yonekubo

et al. 2017

Sci Rep

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Hormonal changes due to menopause can cause various health problems including weight gain and depressive symptoms. Multiple lines of evidence indicate that oestrogen receptors (ERs) play a major role in postmenopausal obesity and depression. However, little is known regarding the ER subtype-specific effects on obesity and depressive symptoms. To delineate potential effects of ERβ activation in postmenopausal women, we investigated the effects of a novel oestrogen receptor β-selective ligand (C-1) in ovariectomized mice. Uterine weight, depressive behaviour, and weight gain were examined in sham-operated control mice and ovariectomized mice administered placebo, C-1, or 17β-oestradiol (E2). Administration of C-1 or E2 reduced body weight gain and depressive-like behaviour in ovariectomized mice, as assessed by the forced swim test. In addition, administration of E2 to ovariectomized mice increased uterine weight, but administration of C-1 did not result in a significant increase in uterine weight. These results suggest that the selective activation of ERβ in ovariectomized mice may have protective effects against obesity and depressive-like behaviour without causing an increase in uterine weight. The present findings raise the possibility of the application of ERβ-ligands such as C-1 as a novel treatment for obesity and depression in postmenopausal women.

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Section: Introductionmentioning

confidence: 88%

“…C-1 was synthesized as described previously 27 . C1 pellets were developed to maintain a plasma concentration within the range (i.e.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Detailed information can be found in ref. 27. Abbreviations : EC50 , half maximal (50%) effective concentration; hER , human estrogen receptor; RBA , relative binding activity.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Sasayama

Sugiyama

Yonekubo

et al. 2017

Sci Rep

Self Cite

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“…In previous studies, we found no PCa in ERβ −/− mice (the original Oliver Smithies ERβ knockout mouse), but there were regions of epithelial hyperplasia, inflammation, increased expression of Bcl2, and reduced differentiation of the epithelial cells (13). Several ERβ-selective agonists have been synthesized (14)(15)(16)(17)(18)(19)(20), and they have been found to be antiinflammatory in the brain and the gastrointestinal tract (21,22) and antiproliferative in cell lines (23)(24)(25)(26)(27) and cancer models (23,28). We have previously shown that there is an increase in p63-positive cells in ERβ −/− mouse VP but that these cells were not confined to the basal layer but were interdispersed with the basal and luminal layer (13).…”

mentioning

confidence: 97%

Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate

Maneix

Insunza

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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As estrogen receptor β (ERβ) mice age, the ventral prostate (VP) develops increased numbers of hyperplastic, fibroplastic lesions and inflammatory cells. To identify genes involved in these changes, we used RNA sequencing and immunohistochemistry to compare gene expression profiles in the VP of young (2-mo-old) and aging (18-mo-old) ERβ mice and their WT littermates. We also treated young and old WT mice with an ERβ-selective agonist and evaluated protein expression. The most significant findings were that ERβ down-regulates androgen receptor (AR) signaling and up-regulates the tumor suppressor phosphatase and tensin homolog (PTEN). ERβ agonist increased expression of the AR corepressor dachshund family (DACH1/2), T-cadherin, stromal caveolin-1, and nuclear PTEN and decreased expression of RAR-related orphan receptor c, Bcl2, inducible nitric oxide synthase, and IL-6. In the ERβ mouse VP, RNA sequencing revealed that the following genes were up-regulated more than fivefold: Bcl2, clusterin, the cytokines CXCL16 and -17, and a marker of basal/intermediate cells (prostate stem cell antigen) and cytokeratins 4, 5, and 17. The most down-regulated genes were the following: the antioxidant gene glutathione peroxidase 3; protease inhibitors WAP four-disulfide core domain 3 (WFDC3); the tumor-suppressive genes T-cadherin and caveolin-1; the regulator of transforming growth factor β signaling SMAD7; and the PTEN ubiquitin ligase NEDD4. The role of ERβ in opposing AR signaling, proliferation, and inflammation suggests that ERβ-selective agonists may be used to prevent progression of prostate cancer, prevent fibrosis and development of benign prostatic hyperplasia, and treat prostatitis.

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Palladium‐Catalyzed Ring‐Opening Diarylation of Cyclobutanols for the Synthesis of Acylindanes

Yan

Liao

et al. 2023

Adv Synth Catal

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Synthesis and structure–activity relationships of 1-benzylindane derivatives as selective agonists for estrogen receptor beta

Cited by 15 publications

References 35 publications

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate

Palladium‐Catalyzed Ring‐Opening Diarylation of Cyclobutanols for the Synthesis of Acylindanes

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