WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent

Hughes, Zoë A.; Liu, Feng; Platt, Brian J.; Dwyer, Jason M.; Pulicicchio, Claudine; Zhang, Guoming; Schechter, Lee E.; Rosenzweig‐Lipson, Sharon; Day, Mark L.

doi:10.1016/j.neuropharm.2008.03.004

Cited by 72 publications

(59 citation statements)

References 48 publications

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“…ERb has also been implicated in brain function and aging (Foster 2012, Handa et al 2012. It was shown to have anxiolytic and antidepressant effects, which may be useful in affective disorders (Hughes et al 2008). ERb agonist was also shown to improve survival in animal models of severe sepsis due to its protective effects on gastrointestinal barrier function (Cristofaro et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Chan

Leung

Chan

et al. 2014

Journal of Endocrinology

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Ovarian cancer cells express both estrogen receptor a (ERa) and ERb, and hormonal therapy is an attractive treatment option because of its relatively few side effects. However, estrogen was previously shown to have opposite effects in tumors expressing ERa compared with ERb, indicating that the two receptor subtypes may have opposing effects. This may explain the modest response to nonselective estrogen inhibition in clinical practice. In this study, we aimed to investigate the effect of selectively targeting each ER subtype on ovarian cancer growth. Ovarian cancer cell lines SKOV3 and OV2008, expressing both ER subtypes, were treated with highly selective ER modulators. These results were confirmed on a xenograft model where SKOV3 cells were injected s.c. into ovariectomized mice. We observed that the average size of xenografts in both the DPN-treated group and the MPP-treated group was significantly smaller than that for the vehicle-treated group. In addition, we found that phospho-AKT expressions in SKOV3 cells were reduced by 80% after treatment with MPP and DPN, indicating that the AKT pathway was involved. The combined treatment with MPP and DPN had a synergistic effect in suppressing ovarian cancer cell growth. Our findings indicate that targeting ER subtypes may enhance the response to hormonal treatment in women with ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Chan

Leung

Chan

et al. 2014

Journal of Endocrinology

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“…Increased anxiety was observed in ERb-deficient female mice (Krezel et al, 2001). ERb specific agonists such as DPN and WAY-200070 have anxiolytic activities in multiple anxiety related tasks in both male and female mice (Hughes et al, 2008;Lund et al, 2005). ERb is highly expressed in the paraventricular nucleus in hyptothalamus (Laflamme et al, 1998;Shughrue et al, 1997) and ERb agonists can reduce stress-induced increases in corticosterone and ACTH levels in mice (Lund et al, 2006;Oyola et al, 2012;Weiser et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Effects of lorazepam and WAY-200070 in larval zebrafish light/dark choice test

Chen

Liu

et al. 2015

Neuropharmacology

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“…E2 was shown to have an antidepressant effect in various strains of ovariectomized mice but lack of effect in ERβ deficient (BERKO) mice, suggesting a specific role of ERβ in mood and behaviour [411]. The ERβ-selective agonists, WAY-200070 and DPN, showed efficacy in animal models of anxiety and depression, having effects on the dopamine and the serotonergic systems while the ERα-selective agonist, PPT, was without effect [412,413,408,[414][415][416]. Cognitive processes are influenced by E2, and in ovariectomized wild-type but not BERKO mice, E2 and DPN showed improved recognition task performance, implicating a more important role of ERβ than ERα in cognitive processes [417].…”

Section: The Central Nervous System and The Hypothalamo-pituitary Axismentioning

confidence: 99%

“…Ligands with ER subtype-selective affinity and biological activity have been reported [113,284,272,285,390,283,115,413,482,385,341,472,355,464,471,414,410,286,412,418,420,407,426,477]. A herbal extract with roughly similar affinity to both ERα and ERβ but with ERβ-selective transcriptional and biological activity has been described [439,446].…”

Section: Development Of Estrogen Receptor Subtype-selective Ligandsmentioning

confidence: 99%

Estrogen Receptors: Their Actions and Functional Roles in Health and Disease

Nilsson

Gustafsson²

2010

Nuclear Receptors

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Abstract:Our view of estrogen signalling has undergone a paradigm shift over the recent 10-15 years with the discovery of a second estrogen receptor, ERβ, in 1995 and the finding that estrogens play an important role also in male physiology. Aromatase deficient patients and aromatase knock-out mice have highlighted the importance of estrogens in development and metabolic homeostasis while ER knock-out mice, ERα-/-and ERβ-/-, have shown that both ERs are of physiological importance and that ERα and ERβ have distinct and non-overlapping functions in the body. The uses of ER subtype-selective ligands in various animal models have further substantiated the distinctive physiological roles of ERα and ERβ and shown that they, in many contexts, are antagonistic against one another. Structural studies of the ligand-binding domains of ERα and ERβ have provided in-depth information on ligand recognition, receptor activation, and recruitment of coregulators. The cloning of coregulators and chromatin modulators together with sophisticated methodology to study gene regulation has significantly increased our understanding of cellular and target gene responses to estrogens, SERMs, and ER subtype-selective ligands. This book chapter will review our current understanding of the mechanisms of ERα-and ERβ-dependent estrogen signalling, the role of ERα and ERβ in health and disease, and the potential clinical uses of ERα-and ERβ-selective pharmaceuticals. INTRODUCTION AND HISTORICAL PERSPECTIVEIn the late nineteenth century two scientists made the observation that female sex steroid hormones played an essential role in promoting mammary tumour growth [1,2]. A little more than half a century later the pioneering endocrinologists, Jensen and Jacobsen [3,4], arrived at the conclusion that the biological effects of 17β-estradiol (E2) could be mediated through a specific receptor rather than through enzymatic metabolism of estradiol itself. A few years later the groups of Gorski and Jensen isolated and characterized an estrogen-binding protein from the uterus and proposed a model for its mechanism of action [5][6][7]. For many years this protein and 91

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WAY-200070, a selective agonist of estrogen receptor beta as a potential novel anxiolytic/antidepressant agent

Cited by 72 publications

References 48 publications

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Targeting estrogen receptor subtypes (ERα and ERβ) with selective ER modulators in ovarian cancer

Effects of lorazepam and WAY-200070 in larval zebrafish light/dark choice test

Estrogen Receptors: Their Actions and Functional Roles in Health and Disease

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