Chemokines (CXCR3) and their ligands (CXCL9, CXCL10, and CXCL11) exert exquisite control over T-cell trafficking and are critical for activation, differentiation and effector T cell function[3].NBI-74330 is a potent antagonist for CXCR3, and exhibits potent inhibition of (125I)CXCL10 and (125I)CXCL11 specific binding with Ki of 1.5 and 3.2 nM, respectively. BI-74330 demonstrates potent inhibition of [125I]CXCL11 specific binding to membranes prepared from transfected CHO cells expressing CXCR3 (CXCR3-CHO) (Ki=3.6 nM). NBI-74330 is 12- and 3.5-fold more potent than CXCL9 (Ki=45.2 nM) and CXCL10 (Ki=12.5 nM), respectively, at inhibiting [125I]CXCL11 binding to CXCR3-CHO cell membranes. NBI-74330 inhibits calcium mobilization in response to CXCL11 and CXCL10 with an IC50 value of 7 nM for both ligands used at their EC80 concentrations (1 nM for CXCL11 and 30 nM for CXCL10). NBI-74330 specifically inhibits CXCR3-mediated calcium mobilization. NBI-74330 also dose-dependently inhibits CXCL11-induced [35S]GTPγS binding in membranes of cells endogenously expressing CXCR3 (H9 cells, IC50 value 5.5 nM). BI-74330 inhibits CXCL11-induced chemotaxis in these cells with an IC50 of 3.9 nM[4]. Administration of NBI-74330 to mice resulted in the formation of an N-oxide metabolite, also an antagonist of CXCR3. Both antagonists were detectable up to 7 h post oral dose and 24 h post subcutaneous dose. Measurement of CXCR3 internalization demonstrated significant antagonism of this response ex vivo, 24 h following subcutaneous administration of NBI-74330[5].Antagonizing CXCR3 with NBI-74330 resulted in a significant reduction in CD4+ T cell and macrophage migration to the peritoneal cavity, which was as shown in ex vivo migration studies totally CXCR3 dependent. Atherosclerotic lesion formation in the aortic valve leaflet area and the entire aorta was significantly inhibited in NBI-74330 treated mice. Lymph nodes draining from the aortic arch were significantly smaller in treated mice and were enriched in regulatory T cells and contained fewer activated T cells, whereas the markers for regulatory T cells within the lesion were enhanced after NBI-74330 treatment[6].
NBI-74330 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Astroglial cells
100 nM
24 hours
To investigate the effect of NBI-74330 on the release of pronociceptive factors by astroglial cells. Results showed that NBI-74330 reduced the expression of CCL4 and CXCL9.
Int J Mol Sci. 2021 Oct 14;22(20):11074
Microglial cells
100 nM
24 hours
To investigate the effect of NBI-74330 on the release of pronociceptive factors (IL-1β, IL-18, CCL6-7, CXCL4, CXCL9-10) by microglial cells. Results showed that NBI-74330 significantly reduced the expression of these factors.
Int J Mol Sci. 2021 Oct 14;22(20):11074
DO11.10 cells
30-300 nM
60 minutes
To evaluate the antagonistic effect of NBI-74330 on CXCL11-induced CXCR3 internalization. Results showed that NBI-74330 at 30-300 nM significantly right-shifted the CXCL11 E/[A] curve.
Br J Pharmacol. 2007 Dec;152(8):1260-71
NBI-74330 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Rats
Chronic constriction injury of the sciatic nerve (CCI)
Intrathecal injection
10 µg/5 µL
16 and 1 hour before CCI, then once daily for 7 days
To investigate the effect of NBI-74330 on mechanical and thermal hypersensitivity in CCI model rats. Results showed that NBI-74330 significantly alleviated mechanical and thermal hypersensitivity and reduced the expression of pronociceptive factors in the spinal cord and dorsal root ganglia.
Int J Mol Sci. 2021 Oct 14;22(20):11074
Balb/c mice
Balb/c mice
Oral or subcutaneous injection
100 mg/kg
Single dose
To evaluate the pharmacokinetic and pharmacodynamic properties of NBI-74330 in mice. Results showed that the N-oxide metabolite of NBI-74330 exhibited CXCR3 antagonistic activity in vivo, and significant antagonism was observed 24 hours after subcutaneous administration.
Br J Pharmacol. 2007 Dec;152(8):1260-71
Mice
GL261 murine model of malignant glioma
Subcutaneously injected
100 mg/kg/day
Daily for 12 days
NBI-74330 prolonged median survival times of both tumor-bearing WT and CXCR3-deficient mice when compared with vehicle-treated groups. NBI-74330 treatment did not impact tumor infiltration of lymphocytes and microglia.
Carcinogenesis. 2011 Feb;32(2):129-37
Mice
Dry skin and allergic contact dermatitis models
Intrathecal injection
20 μg
Single injection
NBI-74330 significantly reduced scratching behavior, indicating that spinal CXCR3 plays an important role in dry skin-induced chronic itch.
Neurosci Bull. 2018 Feb;34(1):54-63
Medaka (Oryzias latipes)
Osteoporosis model
Fish medium
30 μM
3 hours prior to heat shock, continued throughout the experiment
NBI-74330 reduces macrophage recruitment and osteoclast formation by inhibiting Cxcr3.2, protecting bone integrity
Proc Natl Acad Sci U S A. 2020 Aug 11;117(32):19276-19286
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