PD123319
(Synonyms: (S)-(+)-PD 123319) 目录号 : GC16394
PD123319 是血管紧张素 II 受体的非肽类抑制剂，IC50 值为 34nM 。
Cas No.:130663-39-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Neuro-2aneuroblastoma cells |
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Preparation Method |
Neuro-2a cells were incubated for 24-h in a 37 °C incubator, and then treated for another 24-h with designed concentrations of PD123319. Optical density (OD) was measured at 570 nm. |
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Reaction Conditions |
100μM PD123319 for 24 hours |
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Applications |
Significant reduction in cell viability was observed when Neuro-2a cells were treated with the concentration of PD123319 (100 μM). |
| Animal experiment [2]: | |
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Animal models |
LDL receptor -/- mice that were either wild type or deficient for AT2 receptors |
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Preparation Method |
Osmotic minipumps were implanted subcutaneously to deliver saline, AngII (500 ng/kg/min), or PD123319 (3 mg/kg/d ) |
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Dosage form |
Osmotic minipump, 3 mg/kg/d |
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Applications |
PD123319 acts through an angiotensin type 2(AT2) receptor-independent mechanism in angiotensin II -induced vasoconstriction in mice. PD123319 significantly increased Ang II-induced suprarenal aortic (AAAs) independent of AT2 receptors. |
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References: [1]. Y.J. Chen, Z.M. Qian, Y. Sheng, J. Zheng, Y. Liu. Angiotensin II down-regulates transferrin receptor 1 and ferroportin 1 expression in neuro-2a cells via activation of type-1 receptor. Neurosci. Lett., 716 (2020), p. 134684, 10.1016/j.neulet.2019.134684 [2]. Daugherty A, Rateri DL, Howatt DA, Charnigo R, Cassis LA. PD123319 augments angiotensin II-induced abdominal aortic aneurysms through an AT2 receptor-independent mechanism. PLoS One. 2013; 8:e61849. doi: 10.1371/journal.pone.0061849. |
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PD123319 is a non-peptide inhibitor of angiotensin II receptor with IC50 value of 34nM [1].
PD123319 is an antagonist of angiotensin II receptor, unlike previous drugs act as inhibitors of the formation of Ang II. PD123319 shows inhibition potency in both rat adrenal and brain binding assay with IC50 values of 34nM and 210nM, respectively. It is found to prevent Ang II from binding the bovine zona glomerulosa microsomal preparation with IC50 value of 6.9nM in the binding assay using microsome. [2,3]. PD123319 inhibited AT2 amplification product from rat pheochromocytoma cells (PC12w) binding to 0.5 nM 125I-[Sar1, Ile8]-Ang II with IC50 values of 1.7±0.2 nM [4] .In addition, it is reported that administration of PD123319 can suppress the generation of cyclic guanosine monophosphate and increase the production of prostaglandin E2[2,3].
PD123319 was transfused intra-brachial arterial in healthy young volunteers to investigated forearm vascular responses and systemic blood pressure responses. There are significant increases in mean arterial pressure were observed during intra-brachial arterial infusions of PD123319 (p = 0.003) during both placebo (80±9 to 92±17 mmHg) and telmisartan (80±11 to 90±14 mmHg) therapy, possibly in locations other than the forearm resistance vessels. Intra-brachial arterial infusion of PD123319 (10 μg/min) has significant systemic effects on rising mean arterial pressure [5].
References:
[1] Blankley C J, Hodges J C, Klutchko S R, et al.? Synthesis and structure-activity relationships of a novel series of non-peptide angiotensin II receptor binding inhibitors specific for the AT2 subtype. Journal of medicinal chemistry, 1991, 34(11): 3248-3260.
[2] Boulay G, Servant G, Luong T T, et al.? Modulation of angiotensin II binding affinity by allosteric interaction of polyvinyl sulfate with an intracellular domain of the DuP-753-sensitive angiotensin II receptor of bovine adrenal glomerulosa. Molecular pharmacology, 1992, 41(4): 809-815.
[3] Siragy H.? Angiotensin II receptor blockers: review of the binding characteristics. The American journal of cardiology, 1999, 84(10): 3-8.
[4] Kambayashi, Y., Takahashi, K., Bardhan, S. et al.?Molecular structure and function of angiotensin type2 receptor, Kidney Inr, 1994, 46, 1502- 1504.
[5] Daugherty A, Rateri DL, Howatt DA, Charnigo R, Cassis LA. PD123319 augments angiotensin II-induced abdominal aortic aneurysms through an AT2 receptor-independent mechanism. PLoS One. 2013; 8:e61849. doi: 10.1371/journal.pone.0061849.
PD123319 是血管紧张素 II 受体的非肽类抑制剂，IC50 值为 34nM [1]。
PD123319 是一种血管紧张素 II 受体拮抗剂，不同于以往的药物作为血管紧张素 II 形成抑制剂的作用。 PD123319 在大鼠肾上腺和脑结合试验中显示出抑制效力，IC50 值分别为 34nM 和 210nM。在使用微粒体的结合试验中发现它可以阻止 Ang II 与牛球状带微粒体制剂结合，IC50 值为 6.9nM。 [2,3]。 PD123319 抑制大鼠嗜铬细胞瘤细胞 (PC12w) 的 AT2 扩增产物与 0.5 nM 125I-[Sar1, Ile8]-Ang II 结合，IC50 值为 1.7±0.2 nM [4] .此外，据报道PD123319给药可抑制环磷酸鸟苷的产生，增加前列腺素E2的产生[2,3]。
PD123319 被注入健康年轻志愿者的肱动脉内，以研究前臂血管反应和全身血压反应。在安慰剂（80±9 至 92±17 mmHg）和替米沙坦（80±11 至 90±14 mmHg）治疗期间，肱动脉内输注 PD123319 (p = 0.003) 期间观察到平均动脉压显着升高，可能在前臂阻力血管以外的位置。肱动脉内输注 PD123319 (10 μg/min) 对升高平均动脉压具有显着的全身作用[5]。
| Cas No. | 130663-39-7 | SDF | |
| 别名 | (S)-(+)-PD 123319 | ||
| 化学名 | (6S)-1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(2,2-diphenylacetyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-6-carboxylic acid | ||
| Canonical SMILES | CC1=C(C=CC(=C1)CN2C=NC3=C2CC(N(C3)C(=O)C(C4=CC=CC=C4)C5=CC=CC=C5)C(=O)O)N(C)C | ||
| 分子式 | C31H32N4O3 | 分子量 | 508.61 |
| 溶解度 | ≥ 22.4mg/mL in DMSO, ≥ 140 mg/mL in EtOH, ≥ 104.2 mg/mL in Water | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.9661 mL | 9.8307 mL | 19.6614 mL |
| 5 mM | 0.3932 mL | 1.9661 mL | 3.9323 mL |
| 10 mM | 0.1966 mL | 0.9831 mL | 1.9661 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
PD123319, angiotensin II type II receptor antagonist, inhibits oxidative stress and inflammation in 2, 4-dinitrobenzene sulfonic acid-induced colitis in rat and ameliorates colonic contractility
Angiotensin II, the main effector of renin angiotensin system, plays an important role in the inflammatory process and most of its effects are mediated through the AT1 receptor activation. However, the knowledge about the AT2 receptor involvement in this process is still evolving. We previously found that in an experimental model of colitis, AT2 receptor activation can contribute to the impairment of the muscle contractility in vitro in the course of inflammation. Here, we investigated the potential alleviating effects of the in vivo treatment of PD123319 (1-[[4-(Dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid ditrifluoroacetate), AT2 receptor antagonist, in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat model of colitis. The effects of i.p PD123319 (0.3, 3 and 10 mg/kg) administration to rats subjected to intra-rectal DNBS instillation were investigated. The study revealed that the colon injury and the inflammatory signs were ameliorated by PD123319 when visualized by the histopathological examination. The colon shortening, myeloperoxidase activity, and colonic expression of IL-1β, IL-6 and iNOS were downregulated in a dose-dependent manner in DNBS-induced colitis rats treated with PD123319 and the anti-oxidant defense machinery was also improved. The mechanism of these beneficial effects was found in the ability of PD123319 to inhibit NF-κB activation induced by DNBS. The colonic contractility in inflamed tissues was also improved by PD123319 treatment. In conclusion, our data have demonstrated previously that undescribed proinflammatory effects for the AT2 receptors in DNBS-induced colitis in rats in which they are mediated likely by NF-κB activation and reactive oxygen species generation. Moreover, when the inflammatory process is mitigated by the AT2 receptor antagonist treatment, the smooth muscle is able to recover its functionality.
PD123319 augments angiotensin II-induced abdominal aortic aneurysms through an AT2 receptor-independent mechanism
Background: AT2 receptors have an unclear function on development of abdominal aortic aneurysms (AAAs), although a pharmacological approach using the AT2 receptor antagonist PD123319 has implicated a role. The purpose of the present study was to determine the role of AT2 receptors in AngII-induced AAAs using a combination of genetic and pharmacological approaches. We also defined effects of AT2 receptors in AngII-induced atherosclerosis and thoracic aortic aneurysms.
Methods and results: Male AT2 receptor wild type (AT2 +/y) and deficient (AT2 -/y) mice in an LDL receptor -/- background were fed a saturated-fat enriched diet, and infused with either saline or AngII (500 ng/kg/min). AT2 receptor deficiency had no significant effect on systolic blood pressure during AngII-infusion. While AngII infusion induced AAAs, AT2 receptor deficiency did not significantly affect either maximal width of the suprarenal aorta or incidence of AAAs. The AT2 receptor antagonist PD123319 (3 mg/kg/day) and AngII were co-infused into male LDL receptor -/- mice that were either AT2 +/y or -/y. PD123319 had no significant effect on systolic blood pressure in either wild type or AT2 receptor deficient mice. Consistent with our previous findings, PD123319 increased AngII-induced AAAs. However, this effect of PD123319 occurred irrespective of AT2 receptor genotype. Neither AT2 receptor deficiency nor PD123319 had any significant effect on AngII-induced thoracic aortic aneurysms or atherosclerosis.
Conclusions: AT2 receptor deficiency does not affect AngII-induced AAAs, thoracic aortic aneurysms and atherosclerosis. PD123319 augments AngII-induced AAAs through an AT2 receptor-independent mechanism.
Long-term treatment of spontaneously hypertensive rats with PD123319 and electrophysiological remodeling of left ventricular myocardium
To investigate the effects of PD123319, an antagonist of angiotensin II subtype-2 receptor (AT2R), on the electrophysiological characteristics of the left ventricular hypertrophic myocardium in spontaneously hypertensive rats (SHR). A total of twenty-four 10-week-old male SHR were divided into two groups: PD123319 and non-PD123319 groups (n = 12 in each). Twelve 10-week-old Wistar-Kyoto rats served as the control group. Systolic blood pressure, left ventricular mass index (LVMI), ventricular effective refractory period, and ventricular fibrillation threshold were also measured after 8 weeks. I Na, I CaL, I to, and membrane capacitance were measured in the left ventricular myocytes after 8 weeks by whole-cell patch clamp. PD123319 increased LVMI compared with the non-PD123319 group (PD123319 vs. non-PD123319, 3.83 ± 0.11 vs. 3.60 ± 0.19 mg/g; P < 0.01). PD123319 also decreased the ventricular fibrillation threshold compared with the non-PD123319 group (PD123319 vs. non-PD123319, 14.75 ± 0.65 vs. 16.0 ± 0.86 mA; P < 0.01). PD123319 enhanced membrane capacitance compared with the non-PD123319 group (PD123319 vs. non-PD123319, 283.63 ± 5.80 vs. 276.50 ± 4.28 pF; P < 0.05). PD123319 increased the density of I CaL compared with the non-PD123319 group (PD123319 vs. non-PD123319, -6.76 ± 0.48 vs. -6.13 ± 0.30 pA/pF; P < 0.05). PD123319 decreased the density of I to compared with the non-PD123319 group (PD123319 vs. non-PD123319, 11.49 ± 0.50 vs. 12.23 ± 0.36 pA/pF; P < 0.05). Long-term treatment with PD123319 worsened the development of myocyte hypertrophy and associated electrophysiological alterations in spontaneously hypertensive rat.
Angiotensin II type 2 receptor blocker PD123319 has more beneficial effects than losartan on ischemia-reperfusion injury and oxidative damage in isolated rat heart
Our study aimed to determine the effects of losartan and PD123319 in ischemia-reperfusion (IR) injury in isolated perfused rat heart. The study used 40 male Wistar albino rats that were grouped as Control, IR, and IR treatment groups that received losartan (20 mg/kg), PD123319 (20 mg/kg), and losartan+PD123319. The hearts were attached to Langendorff isolated heart system by employing in situ cannulation method, and cardiodynamic parameters were recorded during the experiment. At the end of experiment, hearts were retained for biochemical analysis and all data were statistically evaluated. A partial recovery of cardiodynamic parameters was observed in all treatment groups. A significant increase in oxidative stress parameters were seen in the IR group, whereas all treatment groups exhibited lower increase. Furthermore, levels of all antioxidant parameters were significantly lower in the IR group, but higher in the treatment groups. Effects on all parameters were much more remarkable in the PD123319 group. Levels of angiotensin II and renin were increased (P < 0.001) with IR application and decreased (P < 0.001) with the treatment of both antagonists. In conclusion, treatment of losartan and PD123319 played a cardioprotective role against IR injury, PD123319 being more effective in this protection.
Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice
The renin-angiotensin system modulates insulin action. Angiotensin type 1 receptor exerts a deleterious effects while the angiotensin type 2 receptor (AT2R) appears to have beneficial effects providing protection against insulin resistance and type 2 diabetes. Although recent reports indicate that agonism of AT2R ameliorates diabetes and insulin resistance, the phenotype of AT2R-knockout mice seems to be controversial relating this aspect. Thus, in this study we have explored the role of AT2R in the control of insulin action. To that end, C57Bl/6 mice were administered the synthetic AT2R antagonist PD123319 for 21days (10mg/kg/day ip); vehicle treated animals were used as control. Glucose tolerance, metabolic parameters, in vivo insulin signaling in main insulin-target tissues as well as levels of adiponectin, TNF-α, MCP-1 and IL-6 in adipose tissue were assessed. AT2R blockade with PD123319 induced a marginal effect on glucose homeostasis but an important reduction in the insulin-induced phosphorylation of the insulin receptor and Akt in both liver and adipose tissue. Insulin signaling in skeletal muscle remained unaltered after treatment with PD123319, which could explain the minimal effect on glucose homeostasis induced by PD123319. Our current results reinforce the notion that the AT2R has a physiological role in the conservation of insulin action.