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Y-27632 dihydrochloride Sale

(Synonyms: y-27632, Y27632, Y-27632 dihydrochloride, Y 27632) 目录号 : GC10512

A ROCK inhibitor

Y-27632 dihydrochloride Chemical Structure

Cas No.:129830-38-2

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10mM (in 1mL DMSO)
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实验参考方法

Cell experiment [1]:

Cell lines

umbilical cord blood-derived endothelial progenitor cells

Preparation Method

UCB EPCs (umbilical cord blood-derived endothelial progenitor cells) were cultured in Endothelial Cell Growth Medium-2 (EGM-2) media or conditioned media (CM) from human CECs, with and without the addition of Y-27632 (10 μM).

Reaction Conditions

10 μM;

Applications

Culturing UCB EPCs in conditioned media supplemented with 10 μM Y-27632 resulted in higher proliferation rates compared with EGM-2 media and conditioned media.

Animal experiment [2]:

Animal models

Male balb/c mice

Preparation Method

Male balb/c mice (n=8, for each group) were used in the experiment. Hot-plate latency and the number of writhes were recorded in control and in Y-27632-treated (1-5 mg/kg, i.p.) groups.

Dosage form

1-5 mg/kg, i.p.

Applications

Y-27632 (1 mg/kg) did not affect hot-plate latency; however, it considerably diminished the number of writhes, from 89+/-12 in control to 30+/-6 in the mice treated with 1 mg/kg Y-27632. At a higher dose (5 mg/kg), Y-27632 prolonged the hot-plate latency from 8.7+/-1.0 s to 14.4+/-1.7 s and decreased the number of writhes from 80+/-8 to 24+/-7.

References:

[1]. Zhang W, et al Y-27632 Promotes the Repair Effect of Umbilical Cord Blood-Derived Endothelial Progenitor Cells on Corneal Endothelial Wound Healing. Cornea. 2021 Feb 1;40(2):203-214.

[2]. Büyükafşar K, et al. Rho-kinase inhibitor, Y-27632, has an antinociceptive effect in mice. Eur J Pharmacol. 2006 Jul 10;541(1-2):49-52.

产品描述

Y-27632 dihydrochloride, as a selective Rho-kinase inhibitor, is a novel bronchodilator.[1]

In vitro, treatment with 3 and 10 μM Y-27632 remarkably reduced the maximal contractile response. And Y-27632 (10 μM ) markedly increased the EFS-induced outflow of radioactivity from airway cholinergic nerves by 27% and 54% respectively, in murine and guinea-pig tracheal preparations loaded with [(3)H]-choline.[2] In vitro, Y-27632 at 10 μM abolished stress fibers in Swiss 3T3 cells, but it had no effect in the G(1)-S phase transition of the cell cycle and cytokinesis.[3] In vitro, treatment with 10 μM Y-27632 and hypoxia further increased the expression of ACAN and COL2A1 in chondrocytic cells.[4] In vitro, 100 μM Y-27632 significantly promoted cell proliferation and phagocytosis of trabecular meshwork cells.[6]

In vivo efficacy test it shown that Y-27632 inhalation (1 mM, 2 min) inhibited acetylcholine- or ovalbumin-induced increase in R(L) and had no changes in mean blood pressure, and the effect last for at least 3 h.[1] In vivo experiment it indicated that injection 5mg/kg Y-27632 intravenously markedly decreased the serum levels of interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α) and increased IL-10 level in serum of MRL/lpr mice.[5] In addition, treatment with 2 or 30 mg/kg body weight of Y-27632 orally in SOD1(G93A) mice, Y-27632 improved motor function in male mice at 30 mg/kg, but it had no benefit at 2 mg/kg.[7]

References:
[1]Iizuka K, et al. Evaluation of Y-27632, a rho-kinase inhibitor, as a bronchodilator in guinea pigs. Eur J Pharmacol. 2000 Oct 13;406(2):273-9.
[2]Fernandes L, et al. A Rho-kinase inhibitor, Y-27632, reduces cholinergic contraction but not neurotransmitter release. Eur J Pharmacol. 2006 Nov 21;550(1-3):155-61.
[3]Ishizaki T, et al. Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol. 2000 May;57(5):976-83.
[4]Piltti J, et al. Rho-kinase inhibitor Y-27632 and hypoxia synergistically enhance chondrocytic phenotype and modify S100 protein profiles in human chondrosarcoma cells. Sci Rep. 2017 Jun 16;7(1):3708.
[5]Wang Y, et al. Y-27632, a Rho-associated protein kinase inhibitor, inhibits systemic lupus erythematosus. Biomed Pharmacother. 2017 Apr;88:359-366.
[6]Chen W, et al. Rho-Associated Protein Kinase Inhibitor Treatment Promotes Proliferation and Phagocytosis in Trabecular Meshwork Cells. Front Pharmacol. 2020 Mar 17;11:302.
[7]Günther R, et al. The rho kinase inhibitor Y-27632 improves motor performance in male SOD1(G93A) mice. Front Neurosci. 2014 Oct 7;8:304.

Y-27632 dihydrochloride 作为一种选择性 Rho 激酶抑制剂,是一种新型支气管扩张剂。[1]

在体外,用 3 μM 和 10 μM Y-27632 处理可显着降低最大收缩反应。 Y-27632(10 μM)显着增加 EFS 诱导的气道胆碱能神经放射性流出,分别增加 27% 和 54%,在小鼠和豚鼠气管制剂中加载 [(3)H]-胆碱。[2] 在体外,10 μM 的 Y-27632 消除了 Swiss 3T3 细胞中的应力纤维,但它对细胞周期和胞质分裂的 G(1)-S 相变没有影响。 [3] 在体外,10 μM Y-27632 和低氧处理进一步增加软骨细胞中 ACAN 和 COL2A1 的表达。[4] 在体外,100 μM Y-27632 显着促进小梁网细胞增殖和吞噬作用。[6]

体内功效测试表明,吸入 Y-27632(1 mM,2 分钟)可抑制乙酰胆碱或卵清蛋白诱导的 R(L) 增加,并且平均血压没有变化,并且效果至少持续3 h.[1] 体内实验表明,静脉注射5mg/kg Y-27632可显着降低血清白细胞介素6(IL-6)、IL-1β、肿瘤坏死因子- MRL/lpr 小鼠血清中 α (TNF-α) 和 IL-10 水平升高。[5] 另外,在 SOD1 中口服 2 或 30 mg/kg 体重的 Y-27632 (G93A) 小鼠,Y-27632 在 30 mg/kg 时改善雄性小鼠的运动功能,但在 2 mg/kg 时没有益处。[7]

Chemical Properties

Cas No. 129830-38-2 SDF
别名 y-27632, Y27632, Y-27632 dihydrochloride, Y 27632
化学名 4-[(1R)-1-aminoethyl]-N-pyridin-4-ylcyclohexane-1-carboxamide
Canonical SMILES CC(C1CCC(CC1)C(=O)NC2=CC=NC=C2)N
分子式 C14H21N3O.2HCl 分子量 320.26
溶解度 64mg/mL(199.84mM) in DMSO (warm with 50°C water bath), 64mg/mL(199.84mM) in Water 储存条件 Store at -20°C, protect from light
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Research Update

Evaluation of Y-27632, a rho-kinase inhibitor, as a bronchodilator in guinea pigs

To evaluate (+)-(R)-trans-4-(l-Aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride, monohydrate (Y-27632), a selective Rho-kinase inhibitor, as a novel bronchodilator in vivo and in vitro, we investigated the effect of Y-27632 on the acetylcholine- or ovalbumin-induced increase in lung resistance (R(L)) in non-sensitized or passively sensitized guinea pigs, and the relaxant effects of salbutamol, Y-27632 and theophylline on acetylcholine- or ovalbumin-induced contraction of isolated trachea. Y-27632 inhalation (1 mM, 2 min) inhibited acetylcholine- or ovalbumin-induced increase in R(L) without changes in mean blood pressure, and the effect persisted for at least 3 h. Salbutamol, Y-27632 and theophylline each completely reversed the acetylcholine- or ovalbumin-induced contraction of isolated trachea with rank order of potency, salbutamol>Y-27632>theophylline. The relaxant effect of Y-27632 was not affected by propranolol. We conclude that, although Y-27632 is not as potent as a beta-adrenoceptor agonist, Y-27632 may become an alternative inhaled bronchodilator, because Y-27632 is more potent than theophylline, and the relaxant effect is independent of beta-adrenoceptors.

Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases

Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide++ + dihydrochloride] is widely used as a specific inhibitor of the Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family of protein kinases. This study examined the inhibition mechanism and profile of actions of Y-27632 and a related compound, Y-30141 [(+)-(R)-trans- 4-(1-aminoethyl)-N-(1H-pyrrolo[2, 3-b]pyridin-4-yl)cyclohexan-ecarboxamide dihydrochloride]. Y-27632 and Y-30141 inhibited the kinase activity of both ROCK-I and ROCK-II in vitro, and this inhibition was reversed by ATP in a competitive manner. This suggests that these compounds inhibit the kinases by binding to the catalytic site. Their affinities for ROCK kinases as determined by K(i) values were at least 20 to 30 times higher than those for two other Rho effector kinases, citron kinase and protein kinase PKN. [(3)H]Y-30141 was taken up by cells in a temperature- and time-dependent and saturable manner, and this uptake was competed with unlabeled Y-27632. No concentrated accumulation was found, suggesting that the uptake is a carrier-mediated facilitated diffusion. Y-27632 abolished stress fibers in Swiss 3T3 cells at 10 microM, but the G(1)-S phase transition of the cell cycle and cytokinesis were little affected at this concentration. Y-30141 was 10 times more potent than Y-27632 in inhibiting the kinase activity and stress fiber formation, and it caused significant delay in the G(1)-S transition and inhibition of cytokinesis at 10 microM.

A selective inhibitor of the Rho kinase pathway, Y-27632, and its influence on wound healing in the corneal stroma

Purpose: Our study examined the effect of a selective Rho kinase inhibitor, Y-27632, on corneal wound healing and potential stromal scarring after superficial keratectomy.
Methods: Rabbit keratocytes were induced into myofibroblasts by transforming growth factor β1 (TGFβ1) either with or without Y-27632. Then α-smooth muscle actin (α-SMA) was examined by immunohistochemistry and western blotting, and the contractility of the seeded collagen gels was measured. Y-27632 eye drops (or vehicle only) were administered to eyes after a superficial keratectomy, and the tissue was examined by immunohistochemistry for α-SMA, collagen types I, II, and III, and keratan sulfate. Electron microscopy was conducted with and without histochemical contrasting of sulfated proteoglycans.
Results: Spindle-like cells in culture constituted 99.5±1.1% with TGFβ1 stimulation, but 3.5±1.0% after TGFβ1 and Y-27632 treatment (p<0.01, n=6). α-SMA was seen in 4% of TGFβ1-treated cells, but in only 0.3% of cells with Y-27632 added (p<0.01, n=6), which was confirmed by western blotting. Y-27632 also inhibited the TGFβ1-induced contraction of seeded collagen gels. After superficial keratectomies, collagen type I and keratan sulfate were unchanged by Y-27632 application. Collagen type II was not detected in Y-27632 or vehicle-only corneas. With Y-27632 treatment, α-SMA expression increased and the collagen type III signal became in the weaker subepithelial area. Interestingly, bundles of aligned and uniformly spaced collagen fibrils were more prevalent in keratocytes in Y-27632-treated corneas, which is reminiscent of fibripositor-like structures that have been proposed as a mechanism of matrix deposition in embryonic connective tissues.
Conclusions: Y-27632 inhibits keratocyte-to-myofibroblast transition, and its topical application after a superficial lamellar keratectomy elicits an altered wound healing response, with evidence of an embryonic-type deposition of collagen fibrils.

Mechanical Stretch Promotes Macrophage Polarization and Inflammation via the RhoA-ROCK/NF- κ B Pathway

Macrophages play an essential role in the pathogenesis of most inflammatory diseases. Recent studies have shown that mechanical load can influence macrophage function, leading to excessive and uncontrolled inflammation and even systemic damage, including cardiovascular disease and knee osteoarthritis. However, the molecular mechanism remains unclear. In this study, murine RAW264.7 cells were treated with mechanical stretch (MS) using the Flexcell-5000T Tension System. The expression of inflammatory factors and cytokine release were measured by RT-qPCR, ELISA, and Western blotting. The protein expression of NF-κB p65, Iκb-α, p-Iκb-α, RhoA, ROCK1, and ROCK2 was also detected by Western blotting. Then, Flow cytometry was used to detect the proportion of macrophage subsets. Meanwhile, Y-27632 dihydrochloride, a ROCK inhibitor, was added to knockdown ROCK signal transduction in cells. Our results demonstrated that MS upregulated mRNA expression and increased the secretion levels of proinflammatory factors iNOS, IL-1β, TNF-α, and IL-6. Additionally, MS significantly increased the proportion of CD11b+CD86+ and CD11b+CD206+ subsets in RAW264.7 macrophages. Furthermore, the protein expression of RhoA, ROCK1, ROCK2, NF-κB p65, and IκB-α increased in MS-treated RAW264.7 cells, as well as the IL-6 and iNOS. In contrast, ROCK inhibitor significantly blocked the activation of RhoA-ROCK and NF-κB pathway, decreased the protein expression of IL-6 and iNOS, reduced the proportion of CD11b+CD86+ cells subpopulation, and increased the proportion of CD11b+CD206+ cell subpopulation after MS. These data indicate that mechanical stretch can regulate the RAW264.7 macrophage polarization and enhance inflammatory responses in vitro, which may contribute to activation the RhoA-ROCK/NF-κB pathway.

Rho-kinase inhibitor, Y-27632, has an antinociceptive effect in mice

The possible antinociceptive effect of a Rho-kinase inhibitor, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632), was investigated in mice by using the hot-plate and abdominal constriction response (writhing) tests. In addition, the expression of Rho-kinase protein (ROCK-2) was studied in the mouse brain and spinal cord by Western blotting. Male balb/c mice (n=8, for each group) were used in the experiment. Hot-plate latency and the number of writhes were recorded in control and in Y-27632-treated (1-5 mg/kg, i.p.) groups. Y-27632 (1 mg/kg) did not affect hot-plate latency; however, it considerably diminished the number of writhes, from 89+/-12 in control to 30+/-6 in the mice treated with 1 mg/kg Y-27632 (P=0.001). At a higher dose (5 mg/kg), Y-27632 prolonged the hot-plate latency from 8.7+/-1.0 s to 14.4+/-1.7 s (P=0.005) and decreased the number of writhes from 80+/-8 to 24+/-7 (P=0.002). Western blot analysis revealed that mouse spinal cord and brain homogenates expressed ROCK-2 protein. These results indicate that Rho-kinase may be involved in nociception and that its inhibitors, such as Y-27632, may represent a new type of antinociceptive drug.