A chemokine receptor CCR2 antagonist
The chemokine CCL2, also known as monocyte chemotactic protein-1 (MCP-1), stimulates leukocyte chemotaxis to sites of inflammation via signaling through the MCP-1 receptor, CCR2. RS 102895 is a spiropiperidine compound that acts as a CCR2 antagonist (IC50 = 0.36 ?M).1 It inhibits the related CCR1 receptor with an IC50 value of 17.8 ?M and inhibits adrenergic α1a, α1d, and 5HT1A receptors with IC50 values of 0.13, 0.32, and 47 ?M, respectively.1 RS 102895 prevents chemotaxis of THP-1 cells (IC50 = 1.7 ?M) when MCP-1 is presented as a chemoattractant.1
1.Mirzadegan, T., Diehl, F., Ebi, B., et al.Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: Binding to a common chemokine receptor motif within the helical bundleJ. Biol. Chem.275(33)25562-25571(2000)
Cell experiment: | Transfected mesangial cells (MCs) are serum restricted for 24 h, after which the medium is replaced by serum-free DMEM containing normal glucose (NG; 5.6 mM), NG+Mannitol (NG+M; 24.4 mM), or high glucose (HG; 30 mM). In addition, nontransfected MCs are cultured under NG, NG+M, or HG with or without RS102895 or anti-TGF-1 antibody (25 μg/mL). Nontransfected MCs are also exposed to medium containing recombinant human MCP-1 (10 ng/mL) or recombinant human TGF-1 (2 ng/mL). At 24 h after the media change, cells are harvested and the conditioned culture media are collected[2]. |
Animal experiment: | Rats[3]CCR2 antagonist RS102895 is dissolved in DMSO. Rats receive daily intrathecal injection of either RS102895 (3 g/L) 10 μL or 10 % DMSO 10 μL between 9 and 20 days after operation. All rats are randomLy divided into five groups (n = 10 per group): Sham group, Sham + RS102895 group, BCP group, BCP + RS102895 group, and BCP + DMSO group. Rats are sacrificed 20 days after operation and the tissue samples from the L4-L5 spinal cord segments are rapidly removed and immediately frozen in liquid nitrogen and stored at ?80°C until use for RT-PCR and Western blot[3]. |
参考文献: [1]. Mirzadegan T, et al. Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. J Biol Chem. 2000 Aug 18;275(33):25562-71. | |
动态评分
0.0