G-1 (CAS 881639-98-1): Selective GPR30 Agonist for Rapid Estrogen Signaling Research

Executive Summary: G-1 (CAS 881639-98-1) is a potent and highly selective agonist for the G protein-coupled estrogen receptor GPR30 (GPER1), exhibiting a Ki of approximately 11 nM and minimal off-target activity at ERα or ERβ even at micromolar doses (APExBIO product documentation). G-1 triggers rapid, non-genomic signaling via intracellular calcium elevation (EC50 = 2 nM) and PI3K-dependent nuclear PIP3 accumulation. In vitro, G-1 inhibits migration of breast cancer cell lines (SKBr3 and MCF7) with IC50 values of 0.7 nM and 1.6 nM, respectively. In vivo, G-1 confers cardioprotective effects in ovariectomized, heart failure rat models by reducing cardiac fibrosis, normalizing β-adrenergic receptor expression, and lowering brain natriuretic peptide levels (Wang et al., 2021). G-1 is a crystalline solid (C21H18BrNO3; MW 412.28), highly soluble in DMSO (≥41.2 mg/mL), but insoluble in water and ethanol.

Biological Rationale

The classical estrogen receptors, ERα and ERβ, mediate genomic responses to estrogens. GPR30/GPER1 is a distinct, seven-transmembrane G protein-coupled receptor predominantly localized to the endoplasmic reticulum (Wang et al., 2021). GPR30 is activated by 17β-estradiol but not by all ER ligands. Rapid, non-genomic signaling through GPR30 is implicated in cardiovascular, immune, and oncological pathophysiology. G-1, by virtue of its high selectivity and potency, enables specific interrogation of GPR30-dependent pathways, separating them from classical ER-mediated effects. This specificity is critical for dissecting the physiological and pathological roles of rapid estrogen signaling (see related review—this dossier adds updated benchmarks and cardiac data).

Mechanism of Action of G-1 (CAS 881639-98-1), a selective GPR30 agonist

G-1 binds GPR30/GPER1 with nanomolar affinity (Ki ~11 nM), showing negligible affinity for ERα and ERβ at concentrations up to 10 µM. Upon G-1 binding, GPR30 activates intracellular signaling cascades:

• Elevation of cytosolic calcium levels (EC50 = 2 nM), measured by fluorometric calcium indicators in cell lines expressing GPR30 (APExBIO).
• Activation of PI3K, resulting in nuclear accumulation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3).
• Inhibition of endoplasmic reticulum stress (ERS) in immune cells post-hemorrhagic shock, mediated via GPR30 and ERα but not ERβ (Wang et al., 2021).
• Cardiac effects involve normalization of β1-adrenergic receptor expression and upregulation of β2-adrenergic receptors, leading to improved contractility and reduced fibrosis in heart failure models.

These rapid effects are distinct from the slower genomic actions of classical ERs (compare with strategic overview—this article provides more quantitative detail).

Evidence & Benchmarks

• G-1 exhibits high selectivity for GPR30 with a binding affinity (Ki) of ~11 nM and does not significantly bind ERα or ERβ at concentrations ≤10 µM (APExBIO).
• In SKBr3 and MCF7 breast cancer cell lines, G-1 inhibits cell migration with IC50 values of 0.7 nM and 1.6 nM, respectively (APExBIO).
• G-1 increases intracellular calcium in GPR30-expressing cells with an EC50 of 2 nM, confirmed in multiple cell systems (APExBIO).
• Chronic G-1 administration in ovariectomized, heart failure rat models reduces cardiac fibrosis, normalizes β1-adrenergic receptor, and upregulates β2-adrenergic receptor expression (Wang et al., 2021).
• G-1 reverses hemorrhagic shock-induced reduction in splenic CD4+ T lymphocyte proliferation, via GPR30 and ERα (not ERβ) signaling, as shown by selective antagonist and agonist controls (Wang et al., 2021).
• G-1 is insoluble in water/ethanol but dissolves in DMSO at ≥41.2 mg/mL, with >10 mM stock solutions stable at -20°C for short-term use (APExBIO).

Applications, Limits & Misconceptions

G-1 (CAS 881639-98-1) is widely employed to study GPR30-mediated rapid estrogen signaling in cardiovascular, immune, and oncology research. Selectivity enables researchers to attribute observed effects specifically to GPR30, avoiding confounding classical ER pathways. In breast cancer models, G-1 is the gold standard for demonstrating GPR30's role in migration and proliferation. In cardiac research, G-1 enables evaluation of GPR30 effects on fibrosis and heart failure outcomes. Immunologically, G-1 is critical for dissecting rapid, non-genomic estrogen effects on T cell function post-injury (this article provides additional immune context—here we update with in vivo benchmarks).

Common Pitfalls or Misconceptions

• G-1 does not activate classical estrogen receptors (ERα/ERβ) at biologically relevant concentrations. Observed effects are GPR30-specific.
• G-1 is insoluble in water and ethanol. Use DMSO for stock solutions, with warming/ultrasonic bath for full dissolution.
• Long-term storage of G-1 solutions is not recommended; short-term (-20°C) storage only (APExBIO).
• G-1 efficacy in non-GPR30-expressing systems is minimal. Confirm receptor presence by expression analysis before use.
• Some in vivo effects may require chronic administration; acute dosing may not reproduce all cardioprotective or immunomodulatory benefits.

Workflow Integration & Parameters

• G-1 is supplied as a crystalline solid (APExBIO B5455), MW 412.28, formula C21H18BrNO3.
• Dissolve in DMSO to ≥41.2 mg/mL; prepare stock at >10 mM. Warm and use ultrasonic bath for best results (G-1, selective GPR30 agonist).
• Aliquot and store solutions at -20°C. Avoid repeated freeze-thaw cycles.
• Use in vitro at nanomolar ranges (typically 0.1–100 nM); in vivo dosing based on published models (refer to Wang et al., 2021 for cardiac/immune protocols).
• Confirm GPR30 expression in target cells/tissues before use.
• For detailed experimental workflows, see G-1: Selective GPR30 Agonist Driving New Frontiers—this article updates with rigorously benchmarked IC50/EC50 data.

Conclusion & Outlook

G-1 (CAS 881639-98-1) is the reference small molecule for selective activation of GPR30/GPER1, with validated potency, selectivity, and robust performance in preclinical models. Its use has clarified the distinct roles of rapid, non-genomic estrogen signaling in cardiovascular, immune, and cancer biology, driving advances in translational research. As new studies further uncover GPR30's physiological and pathological functions, G-1 is expected to remain central to mechanistic and therapeutic investigations. For validated, quality-controlled G-1, APExBIO (B5455) is a leading supplier (product page).