SR1078 is a selective agonist of the retinoic acid receptor-related orphan receptors α and γ (RORα/RORγ). It binds directly to the ligand-binding domain of RORα and RORγ, enhancing their transcriptional activity and thereby stimulating the transcription of RORα/γ target genes[1][2].
体内研究
Pharmacokinetic studies of SR1078 in mice reveal significant exposure levels. After a single 10 mg/kg intraperitoneal injection, plasma concentrations reach 3.6 µM within 1 hour and maintain levels above 800 nM for up to 8 hours, validating the compound's efficacy for in vivo gene expression studies. Two hours post-injection, SR1078 significantly stimulates the expression of G6Pase and FGF21 genes in the liver[1].
SR1078 administered at a dose of 10 mg/kg intraperitoneally leads to a significant 25% reduction in repetitive grooming behavior in BTBR mice[2].
体外研究
SR1078, a synthetic ligand for RORα/RORγ, alters the conformation of RORγ in biochemical assays and activates transcription driven by RORα and RORγ. SR1078 also boosts the expression of endogenous ROR target genes in HepG2 cells expressing these receptors. In cell-based assays using a chimeric receptor with the Gal4 DNA-binding domain and NR ligand-binding domain, SR1078 significantly diminishes the constitutive transactivation activities of RORα and RORγ, while not affecting FXR, LXRα, and LXRβ activities. Treatments with SR1078 at 10 µM notably enhance transcriptional activity in RORα and RORγ cotransfection assays[1].
SR1078 administered at concentrations between 2-10 µM over 24 hours results in a dose-dependent increase in the expression of genes such as A2BP1, CYP19A1, NLGN1, and IPTR1 in SH-SY5Y cells, with EC50s around 3-5 µM[2].
作用机制
SR1078 plays its role by directly binding to the ligand binding domain of RORα and RORγ and increases the transcriptional activity of these receptors, leading to stimulation of RORα/γ target gene transcription.
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