| In Vitro | In vitro activity: WAY-200070 (WAY200070) is a novel and selective agonist of the estrogen receptor β (ERRβ) with antidepressant effects. It activates ERRβ with an IC50 of 2.3 nM. Recent studies have reported that estrogen has antidepressant-like effects in animal models. As an ERRβ agonist, WAY-200070 has antidepressant and anxiolytic activities as shown in multiple in vivo mouse models. Upon administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ER beta receptors from the cytosol. WAY-200070 also increased c-fos activation 4h, but not 15 min after administration. Both nuclear translocation and c-fos induction effects of WAY-200070 demonstrate that WAY-200070 has bound to estrogen receptors and triggered downstream events. The absence of these effects in the ER beta KO mice confirms that WAY-200070 was targeting ER beta. Administration of WAY-200070 (30 mg/kg s.c.) produced a delayed approximately 50% increase in dopamine in the striatum of wild type mice.
Kinase Assay: WAY-200070 is a selective agonist of the estrogen receptor β (ERRβ) with an IC50 of 2.3 nM. |
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| In Vivo | Recent studies have reported that estrogen has antidepressant-like effects in animal models. As an ERRβ agonist, WAY-200070 has antidepressant and anxiolytic activities as shown in multiple in vivo mouse models. Upon administration, WAY-200070 (30 mg/kg s.c.) caused the nuclear translocation of striatal ER beta receptors from the cytosol. WAY-200070 also increased c-fos activation 4h, but not 15 min after administration. Both nuclear translocation and c-fos induction effects of WAY-200070 demonstrate that WAY-200070 has bound to estrogen receptors and triggered downstream events. The absence of these effects in the ER beta KO mice confirms that WAY-200070 was targeting ER beta. Administration of WAY-200070 (30 mg/kg s.c.) produced a delayed approximately 50% increase in dopamine in the striatum of wild type mice. The effect was significant and maintained from 90 to 240 min. This increase was absent in ER beta KO mice. In wild type mice, WAY-200070 (30 mg/kg s.c.) also produced a delayed and transient approximately 100% increase in 5-HT. To further investigate the role of ER beta receptors on serotonergic function, 5-HTP accumulation was measured. ER beta KO mice were found to have reduced frontal cortex levels of 5-HTP, indicating reduced tryptophan hydroxylase activity. WAY-200070 (3-30 mg/kg s.c.) was also tested in behavioural models. WAY-200070 (30 mg/kg s.c.) reduced immobility time in the mouse tail suspension test indicating an antidepressant-like effect. WAY-200070 (30 mg/kg) showed anxiolytic-like effects in the four-plate test (increased punished crossings) and stress-induced hyperthermia (attenuation of hyperthermic response). The effects of the selective ER beta agonist, WAY-200070, on dopamine and serotonin, the anxiolytic-like and antidepressant-like effects as well as the genotype specific effects on neurochemistry support that positive modulation of ER beta function may provide a novel treatment for affective disorders. |
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| Animal model | Mouse model with and without ER beta KO; Male ERβKO, ERαKO mice (on C57BL/6 background) and wild type C57BL/6 mice (10- to 12-week-old; Taconic) were used for neurochemistry and in vitro studies. Male Swiss Webster mice (25–35 g, Charles River) were used in the tail suspension test. Male C57Bl/6 mice (25–35 g, Taconic) were used for stress-induced hyperthermia and control microdialysis experiments. |
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| Formulation & Dosage | 3-30 mg/kg; s.c. |
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| References | Neuropharmacology. 2008 Jun;54(7):1136-42. |
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