High-affinity, potent and selective EBI2 (GPR183) antagonist with good pharmacokinetic properties and oral availability in mice in vivo.
NBIR189 is a high-affinity, potent and selective EBI2 (GPR183) antagonist (IC50 = 16 nM against 10 nM 7α,25-OHC for binding human EBI2) that inhibits 7α,25-OHC-induced GTPγS binding (IC50 = 8.5 and 7.0 nM, respectively, against 0.33 and 0.1 nM OHC; human EBI2-expressing CHO membrane), calcium mobilization (IC50 = 11 and 15 nM using human or mouse EBI2-transfected cells, respectively), and chemotaxis (IC50 = 0.3 nM against 20 nM OHC-induced U937 migration). NBIR189 displays no inhibitory potency against 5HT2A, muscarinic acetylcholine receptor M2, adrenoreceptor α1A, nor significant affintiy toward 18 other GPCRs/transporters/enzymes, and exhibits good pharmacokinetic properties and oral availability in mice (AUC = 3608 nmol h/L, Cmax = 835 nM, tmax = 1 h, F = 49%; 3 mg/kg p.o.). A useful tool for probing EBI2-mediated physiological functions and autoimmune disorders.
Biochemical and biophysical research communications, 446(3), 663-668 (2014-02-01)
Oxysterols such as 7 alpha, 25-dihydroxycholesterol (7α,25-OHC) are natural ligands for the Epstein-Barr virus (EBV)-induced gene 2 (EBI2, aka GPR183), a G protein-coupled receptor (GPCR) highly expressed in immune cells and required for adaptive immune responses. Activation of EBI2 by
Arrival of encephalitogenic T cells at inflammatory foci represents a critical step in development of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. EBI2 and its ligand, 7α,25-OHC, direct immune cell localization in secondary lymphoid organs. CH25H and CYP7B1
The interaction between oxysterols and the G protein-coupled receptor Epstein-Barr virus-induced gene 2 (EBI2) fine-tunes immune cell migration, a mechanism efficiently targeted by several disease-modifying treatments developed to treat multiple sclerosis (MS), such as natalizumab. We previously showed that memory
EBI2 is a G protein-coupled receptor activated by oxysterol 7α, 25-dihydroxycholesterol (7α25HC) and regulates T cell-dependant antibody response and B cell migration. We recently found EBI2 is expressed in human astrocytes, regulates intracellular signalling and modulates astrocyte migration. Here, we
Journal of medicinal chemistry, 57(8), 3358-3368 (2014-04-01)
Oxysterols have recently been identified as natural ligands for a G protein-coupled receptor called EBI2 (aka GPR183) ( Nature 2011 , 475 , 524 ; 519 ). EBI2 is highly expressed in immune cells ( J. Biol. Chem. 2006
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