Benzothiophene Selective Estrogen Receptor Modulators Provide Neuroprotection by a Novel GPR30-Dependent Mechanism

Abstract

The clinical benzothiophene SERM (BT-SERM), raloxifene, was compared with estrogens in protection of primary rat neurons against oxygen-glucose deprivation (OGD). Structure-activity relationships for neuroprotection were determined for a family of BT-SERMs displaying a spectrum of ERα and ERβ binding affinity and agonist/antagonist activity, leading to discovery of a neuroprotective pharmacophore, present in the clinically relevant SERMS, raloxifene and desmethylarzoxifene (DMA), for which submicromolar potency was observed for neuroprotection. BT-SERM neuroprotection did not correlate with binding to ER nor classical ER activity, however, both the neuroprotective SERMs and estrogens were shown, using pharmacological probes, to activate the same kinase signaling cascades. The antiestrogen ICI 182,780 inhibited the actions of estrogens, but not those of BT-SERMs, whereas antagonism of the G-protein coupled receptor, GPR30, was effective for both SERMs and estrogens. Since SERMs have antioxidant activity, ER-independent mechanisms were studied using the classical phenolic antioxidants, BHT and Trolox, and the Nrf2-dependent cytoprotective electrophile, sulforaphane. However, neuroprotection by these agents was not sensitive to GPR30 antagonism. Collectively, these data indicate that the activity of neuroprotective BT-SERMs is GPR30-dependent and ER-independent and not mediated by antioxidant effects. Comparison of novel BT-SERM derivatives and analogs identified a neuroprotective pharmacophore of potential use in design of novel neuroprotective agents with a spectrum of ER activity.

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…RAL exhibits strong GPER efficacy (EC 50 = 10-100 nM), acting as a GPER agonist (Petrie et al, 2013). A series of structurally related benzothiophene derivatives including desmethylarzoxifene, the active bisphenolic metabolite of arzoxifene, was evaluated for the ability to provide neuroprotection of primary cortical neurons in response to oxygenglucose deprivation (Abdelhamid et al, 2011). The ER antagonist ICI 182,780 at 1 mM did not block the neuroprotection afforded by RAL or desmethylarzoxifene, although it did for E2, whereas G15 at 100 nM prevented the neuroprotection elicited by both RAL and E2.…”

Hyperoxia and the Immature Brain

“…E2 antagonises the hyperoxia-induced inactivation of ERK1/2 and Akt, essential kinases of the MAPK and PI3K pathways that promote cell survival [158,159] . In addition, a protective effect of E2 was also shown in immature neurons [160][161][162] and astroglial cells [163,164] . Therefore, maintaining placental E2 plasma levels may be effective in protecting neonates from brain injury.…”

Novel Selective Estrogen Mimics for the Treatment of Tamoxifen-Resistant Breast Cancer

“…The synthesis of BTC and TTC-352 has been described (13). Dansyl derivatization of BTC was employed to increase limits of detection and quantitation for LC-MS/MS analysis of plasma samples (Supplemental Figures 2 and 3).…”