RS 102895 hydrochloride is a potent inhibitor of CCR2, with an IC50 value of 0.36µM[1]. RS 102895 hydrochloride could specifically bind to the β subunit of CCR2 receptor, effectively inhibit CCR2 signaling and monocyte recruitment[2]. RS 102895 hydrochloride has been widely used to reduce inflammation and delay the progression of hypertension in rat models of hypertension[3].
In vitro, RS 102895 hydrochloride treatment (6µM; 24h) significantly inhibited Monocyte chemotactic protein-3 (MCP-3)-induced human coronary artery smooth muscle cell (CASMC) proliferation[4]. Pretreatment of rat aortic smooth muscle cells (SMCs) with 6μM RS 102895 hydrochloride for 2h partially blocked angiotensin II-stimulated (48h) cell proliferation[5]. Pretreatment of SCC4 cells with RS 102895 hydrochloride (100ng/ml) for 30 minutes inhibited MCP-1-stimulated VEGF-A mRNA expression and protein secretion and reduced cell migration[6].
In vivo, 6-week-old db/db mice fed with a diet supplemented with 2mg/kg/day RS 102895 hydrochloride for 9 weeks improved glucose tolerance, and mesangial expansion, glomerular basement membrane thickening, and enhanced desmin staining were significantly improved in mice[7]. A daily intraperitoneal injection of RS 102895 hydrochloride at a dose of 20mg/kg for 5 consecutive days ameliorated the severity of severe murine experimental autoimmune neuritis model[8]. RS 102895 hydrochloride treatment via intraperitoneal injection at a dose of 5mg/kg/day for 21 days ameliorated renal damage and hypertension of male Dahl SS rats with a high-salt diet[9].
References:
[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 bundle[J]. Journal of Biological Chemistry, 2000, 275(33): 25562-25571.
[2] Mitchell L A, Hansen R J, Beaupre A J, et al. Optimized dosing of a CCR2 antagonist for amplification of vaccine immunity[J]. International immunopharmacology, 2013, 15(2): 357-363.
[3] Elmarakby A A, Quigley J E, Olearczyk J J, et al. Chemokine receptor 2b inhibition provides renal protection in angiotensin II–salt hypertension[J]. Hypertension, 2007, 50(6): 1069-1076.
[4] Maddaluno M, Di Lauro M V, Di Pascale A, et al. Monocyte chemotactic protein-3 induces human coronary smooth muscle cell proliferation[J]. Atherosclerosis, 2011, 217(1): 113-119.
[5] Yao H L, Gao F H, Li Z Z, et al. Monocyte chemoattractant protein-1 mediates angiotensin II-induced vascular smooth muscle cell proliferation via SAPK/JNK and ERK1/2[J]. Molecular and cellular biochemistry, 2012, 366(1): 355-362.
[6] Lien M Y, Chang A C, Tsai H C, et al. Monocyte chemoattractant protein 1 promotes VEGF-A expression in OSCC by activating ILK and MEK1/2 signaling and downregulating miR-29c[J]. Frontiers in oncology, 2020, 10: 592415.
[7] Seok S J, Lee E S, Kim G T, et al. Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice[J]. Nephrology Dialysis Transplantation, 2013, 28(7): 1700-1710.
[8] Yuan F, Yosef N, Lakshmana Reddy C, et al. CCR2 gene deletion and pharmacologic blockade ameliorate a severe murine experimental autoimmune neuritis model of Guillain-Barre syndrome[J]. PloS one, 2014, 9(3): e90463.
[9] Alsheikh A J, Dasinger J H, Abais-Battad J M, et al. CCL2 mediates early renal leukocyte infiltration during salt-sensitive hypertension[J]. American Journal of Physiology-Renal Physiology, 2020, 318(4): F982-F993.
RS 102895 hydrochloride是一种有效的CCR2抑制剂，IC50值为0.36µM[1]。RS 102895 hydrochloride能特异性结合CCR2受体的β亚基，有效抑制CCR2信号通路及单核细胞募集[2]。RS 102895 hydrochloride已广泛应用于高血压大鼠模型中，用于减轻炎症反应及延缓高血压进展[3]。
在体外，使用6µM的RS 102895 hydrochloride处理24小时，可显著抑制单核细胞趋化蛋白-3诱导的人冠状动脉平滑肌细胞(CASMC)增殖[4]。用6μM的RS 102895 hydrochloride预处理大鼠主动脉平滑肌细胞(SMCs) 2小时，能部分阻断血管紧张素II刺激的细胞增殖[5]。以100ng/ml的RS 102895 hydrochloride预处理SCC4细胞30分钟，可抑制单核细胞趋化蛋白-1刺激的VEGF-A mRNA表达及蛋白分泌，并降低细胞迁移能力[6]。
在体内，给6周龄db/db小鼠饲喂添加2mg/kg/day的RS 102895 hydrochloride饮食连续9周，可改善葡萄糖耐受性，并显著减轻系膜扩张、肾小球基底膜增厚等病理改变，同时增强结蛋白染色强度[7]。连续5天每日腹腔注射20mg/kg剂量的RS 102895 hydrochloride，能减轻小鼠实验性自身免疫性神经炎模型的疾病严重程度[8]。通过每日腹腔注射5mg/kg/day剂量的RS 102895 hydrochloride连续21天，可改善高盐饮食雄性Dahl SS大鼠的肾功能损伤及高血压症状[9]。