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CCR2-RA-[R]

Catalog No.GC31714

CCR2-RA -[R] can inhibit CCR2 in a non-competitive binding manner, mainly by blocking activation-related conformational changes and the formation of G-protein binding interfaces.

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CCR2-RA-[R] Chemical Structure

Cas No.: 512177-83-2

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10mM (in 1mL DMSO)
$89.00
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5mg
$81.00
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10mg
$129.00
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25mg
$258.00
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50mg
$441.00
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100mg
$698.00
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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment [1]:

Preparation Method

For dissociation experiments, the membranes were first incubated with 3 nM CCR2-RA-[R]CCR2-RA-[R] for 90 minutes. Dissociation was initiated by the addition of 10 mM of JNJ-27141491 at different time points.

Reaction Conditions

3 nM [3H]CCR2-RA-[R] for 90 minutes

Applications

CCR2-RA-[R] had IC50 values of 103 + 18. Saturation binding experiments yielded a Kp of 5.8 + 0.2 nM with a Bmax of 9.7 + 0.2 pmol/mg.

Cell experiment [1]:

Cell lines

U2OS-CCR2 cells

Preparation Method

For the antagonist assays, cells were first preincubated for 30 minutes with increasing concentrations of antagonist(including CCR2-RA-[R]) or vehicle control that was added in 5 ul of compound solution (final concentration of 0.25% dimethylsulfoxide).Subsequently, cells were stimulated with an ECso concentration (3 nM) of CCL2.

Reaction Conditions

Increasing concentrations of the antagonists(including CCR2-RA-[R] were added 30 minutes before agonist stimulation to determine their IC 50 value.( No specific concentration)

Applications

INCB3344 competitively inhibited CCL2-induced G protein activation, whereas CCR2-RA-[R] showed a noncompetitive or allosteric mode of inhibition.

Animal experiment [2]:

Animal models

Adult female Sprague-Dawley rats (150-200 g)

Preparation Method

CCR2-RA-[R] were given a one-time intraperitoneal (i.p.) injection one hour prior to behavioral testing.

Dosage form

10 mg/kg CCR2-RA-[R] for 1 time

Applications

CCR2-RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia

References:

[1]. Zweemer AJ, Nederpelt I, ,et,al. Multiple binding sites for small-molecule antagonists at the CC chemokine receptor 2. Mol Pharmacol. 2013 Oct;84(4):551-61. doi: 10.1124/mol.113.086850. Epub 2013 Jul 22. PMID: 23877010.
[2]. Bhangoo S, Ren D,,et,al. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain. 2007 Dec 12;3:38. doi: 10.1186/1744-8069-3-38. PMID: 18076762; PMCID: PMC2228278.

Background

CCR2-RA -[R] can inhibit CCR2 in a non-competitive binding manner, mainly by blocking activation-related conformational changes and the formation of G-protein binding interfaces[1,2]. For CCR2-RA-[R] the most important residues for binding were found to be the highly conserved tyrosine Y(7.53) and phenylalanine F(8.50) of the NPxxYx(5,6)F motif, as well as V(6.36) at the bottom of TM-VI and K(8.49) in helix-VIII[3].

CCR2-RA-[R] had IC50 values of 103 nM.Saturation binding experiments yielded a Kp of 5.8 + 0.2 nM with a Bmax of 9.7 + 0.2 pmol/mg.CCR2-RA-[R] clearly showed noncompetitive antagonism for CCR2 with respect to CCL2, as indicated by a decrease in CCL2's efficacy in the presence of increasing concentrations of CCR2RA-[R][1].

Focal nerve demyelination increased behavioral reflex responsiveness to mechanical stimuli between postoperative day (POD) 3 and POD28 in both the hindpaw ipsilateral and contralateral to the nerve injury. CCR2 RA-[R] treatment of nerve-injured rats produced stereospecific bilateral reversal of tactile hyperalgesia[4]. CCR2i CCR2-RA-[R] (MCP-1 receptor inhibitor) were administered via intraperitoneal injection. With or without PDX, treatment with CCR2-RA-[R] reduced the number of neutrophils and recruited macrophages, indicating that the basic function of PDX was disappeared after using CCR2 inhibitors(CCR2-RA-[R])[5]. CCR2 RA-[R] enhances the response to ¨»PD-1 by promoting the counts of progenitor Tex[6]. Compared to the model group, the fluorescence intensity of spleen was markedly decreased by Pirfenidone and CCR2-RA-[R] Moreover, Compared to the model group, the fluorescence intensity of liver metastasis foci was dramatically reduced by Pirfenidone and CCR2-RA-[R][7].

References:
[1]. Zweemer AJ, Nederpelt I,et,al. Multiple binding sites for small-molecule antagonists at the CC chemokine receptor 2. Mol Pharmacol. 2013 Oct;84(4):551-61. doi: 10.1124/mol.113.086850. Epub 2013 Jul 22. PMID: 23877010.
[2]. Zheng Y, Qin L, ,et,al.Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists. Nature. 2016 Dec 15;540(7633):458-461. doi: 10.1038/nature20605. Epub 2016 Dec 7. PMID: 27926736; PMCID: PMC5159191.
[3]. Zweemer AJ, Bunnik J, ,et,al.Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2. Mol Pharmacol. 2014 Oct;86(4):358-68. doi: 10.1124/mol.114.093328. Epub 2014 Jul 14. PMID: 25024169.
[4]. Bhangoo S, Ren D, ,et,al. Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors. Mol Pain. 2007 Dec 12;3:38. doi: 10.1186/1744-8069-3-38. PMID: 18076762; PMCID: PMC2228278.
[5]. Ye Y, Zhang HW, et,al. PDX regulates inflammatory cell infiltration via resident macrophage in LPS-induced lung injury. J Cell Mol Med. 2020 Sep;24(18):10604-10614. doi: 10.1111/jcmm.15679. Epub 2020 Jul 31. PMID: 32735065; PMCID: PMC7521295.
[6]. Yihua Xu, Hao Wang, et,al. DFB Suppresses Obesity-Driven CRC Via Restricting Progenitor to Terminally Exhausted T Cell Differentiation, 19 October 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-952538/v1]
[7]. Chen C, Yao X, et,al. Dahuang Zhechong Pill suppresses colorectal cancer liver metastasis via ameliorating exosomal CCL2 primed pre-metastatic niche. J Ethnopharmacol. 2019 Jun 28;238:111878. doi: 10.1016/j.jep.2019.111878. Epub 2019 Apr 13. PMID: 30986521.

Chemical Properties

Cas No. 512177-83-2 SDF
Canonical SMILES O=C1C(O)=C(C(C)=O)[C@@H](C2CCCCC2)N1C(C(F)=C3)=CC=C3Cl
Formula C18H19ClFNO3 M.Wt 351.8
Solubility DMSO : ≥ 125 mg/mL (355.32 mM);Water : < 0.1 mg/mL (insoluble) Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 2.8425 mL 14.2126 mL 28.4252 mL
5 mM 0.5685 mL 2.8425 mL 5.685 mL
10 mM 0.2843 mL 1.4213 mL 2.8425 mL
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