D3-βArr is the first small molecule positive allosteric modulator of TSHR. It translocated β-arrestin 1 with EC50 value of 11.6μM, and potentiated the effect of TSH in stimulating β-Arr 1 translocation. It had no agonistic effect on cAMP production nor did it inhibit TSH-induced cAMP production in DiscoverX1 cells or primary cultures of human thyrocytes from five donors in which TSHRs are expressed at physiologic levels. D3-βArr at 10μM potentiated TSH-induced upregulation of ALPL (alkaline phosphatas) and OPN (osteopontin) mRNA levels 1.6-fold and 5.5-fold, respectively, in human U2OS-TSHR cells expressing wild-type TSHRs, which is a model of human preosteoblast-like cells, post 7 days[2].
D3-βArr 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U2OS-TSHR cells
10 μM
7 days
Measure osteoblast-specific gene expression, D3-βArr potentiated TSH-induced upregulation of ALPL and OPN mRNA levels
J Pharmacol Exp Ther. 2018 Jan;364(1):38-45
DiscoverX1 cells
0 to 100 μM
240 min
Measure β-Arr 1 translocation to TSHR, D3-βArr stimulated β-Arr 1 translocation with a 5.1-fold greater efficacy than TSH
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