![CCR2-RA-[R]](https://www.anjiechem.com/public/static/upload/images/goods/2020/08/26/abcgfsdeic12759.png "CCR2-RA-[R]")
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].
参考文献:
[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.
CCR2-RA -[R]能以非竞争性结合的方式抑制CCR2，主要是通过阻断激活相关的构象变化和G蛋白结合界面的形成[1,2] .对于 CCR2-RA-[R]，发现最重要的结合残基是 NPxxYx(5,6)F 基序的高度保守的酪氨酸 Y(7.53) 和苯丙氨酸 F(8.50)，以及 V(6.36) TM-VI 底部和螺旋-VIII 中的 K(8.49)[3].
CCR2-RA-[R] 的 IC50 值为 103 nM。饱和结合实验产生的 Kp 为 5.8 + 0.2 nM，Bmax 为 9.7 + 0.2 pmol/mg。CCR2-RA-[R] 清楚地显示出非竞争性拮抗作用CCR2 相对于 CCL2 的变化，如在 CCR2RA-[R][1] 浓度增加的情况下 CCL2 的功效降低所示。
局灶性神经脱髓鞘增加了神经损伤同侧和对侧后爪在术后第 3 天和 POD28 之间对机械刺激的行为反射反应。 CCR2 RA-[R] 对神经损伤大鼠的治疗产生了触觉痛觉过敏的立体特异性双侧逆转 [4]。 CCR2i CCR2-RA-[R]（MCP-1 受体抑制剂）通过腹膜内注射给药。有或没有 PDX，CCR2-RA-[R] 治疗减少了中性粒细胞的数量并募集了巨噬细胞，表明在使用 CCR2 抑制剂（CCR2-RA-[R]）后 PDX 的基本功能消失了[5 ]。 CCR2 RA-[R] 通过促进祖细胞 Tex[6] 的计数来增强对 ¨?PD-1 的反应。与模型组相比，吡非尼酮和CCR2-RA-[R]脾脏荧光强度显着降低；此外，与模型组相比，吡非尼酮和CCR2-RA-[R]肝转移灶荧光强度显着降低。 R][7].
| 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 |
|
参考文献: [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. | |
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