Rotigaptide
(Synonyms: ZP123) 目录号 : GC39432
Rotigaptide (ZP123) 是连接蛋白 43 (Cx43) 的特异性调节剂。Rotigaptide 可防止 Cx43 介导的间隙连接 (gap junction) 通讯的解偶联，并在急性代谢应激期间使细胞间通讯正常化。Rotigaptide 是一种抗心律失常肽 (AAP)，有潜力用于心律失常-特别是房颤的相关研究。
Cas No.:355151-12-1
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Rotigaptide (ZP123) is a novel and specific modulator of connexin 43 (Cx43). Rotigaptide prevents the uncoupling of Cx43-mediated gap junction communication and normalizes cell-to-cell communication during acute metabolic stress. Rotigaptide is a potent antiarrhythmic peptide (AAP) with improved stability and has the potential for the investigation of cardiac arrhythmias-specifically atrial fibrillation[1][2].
[1]. Seyed Mojtaba Ghiasi, et al. The connexin 43 regulator Rotigaptide reduces cytokine-induced cell death in human islets [2]. Stahlhut M, et al. The antiarrhythmic peptide rotigaptide (ZP123) increases connexin 43 protein expression in neonatal rat ventricular cardiomyocytes.Cell Commun Adhes. 2006 Jan-Apr;13(1-2):21-7. [3]. KjØlbye AL, et al. Pharmacological modulation of gap junction function with the novel compound rotigaptide: a promising new principle for prevention of arrhythmias.Basic Clin Pharmacol Toxicol. 2007 Oct;101(4):215-30.
| Cas No. | 355151-12-1 | SDF | |
| 别名 | ZP123 | ||
| Canonical SMILES | O=C(N)CNC([C@@H](C)NC(CNC([C@@H]1N(C([C@@H]2N(C([C@@H](CC3=CC=C(O)C=C3)NC(C)=O)=O)CCC2)=O)C[C@@H](O)C1)=O)=O)=O | ||
| 分子式 | C28H39N7O9 | 分子量 | 617.65 |
| 溶解度 | Soluble in DMSO | 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 | 1.619 mL | 8.0952 mL | 16.1904 mL |
| 5 mM | 0.3238 mL | 1.619 mL | 3.2381 mL |
| 10 mM | 0.1619 mL | 0.8095 mL | 1.619 mL |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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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。
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Rotigaptide protects the myocardium and arterial vasculature from ischaemia reperfusion injury
Br J Clin Pharmacol 2016 Jun;81(6):1037-45.PMID:26750458DOI:10.1111/bcp.12882.
Aim: Ischaemia-reperfusion injury (IRI) causes impaired endothelial function and is a major component of the adverse effects of reperfusion following myocardial infarction. Rotigaptide increases gap junction conductance via connexin-43. We tested the hypothesis that Rotigaptide reduces experimental myocardial infarction size and ameliorates endothelial IRI in humans. Methods: Myocardial infarction study: porcine myocardial infarction was achieved by catheter-induced occlusion of the left anterior descending artery. In a randomized double-blind study, Rotigaptide (n = 9) or placebo (n = 10) was administered intravenously as a 10 min bolus prior to reperfusion and continuously during 2 h of reperfusion. Myocardial infarction size (IS) was assessed as proportion of the area at risk (AAR). Human translational study: forearm IRI was induced in the presence or absence of intra-arterial Rotigaptide. In a randomized double-blind study, forearm arterial blood flow was measured at rest and during intra-arterial infusion of acetylcholine (5-20 μg min(-1) ; n = 11) or sodium nitroprusside (2-8 mg min(-1) ; n = 10) before and after intra-arterial infusion of placebo or Rotigaptide, and again following IRI. Results: Myocardial infarction study: Rotigaptide treatment was associated with a reduction of infarct size (IS/AAR[%]: 18.7 ± 4.1 [Rotigaptide] vs. 43.6 ± 4.2 [placebo], P = 0.006). Human translational study: Endothelium-dependent vasodilatation to acetylcholine was attenuated after ischaemia-reperfusion in the presence of placebo (P = 0.007), but not in the presence of Rotigaptide (P = NS). Endothelium-independent vasodilatation evoked by sodium nitroprusside was unaffected by IRI or Rotigaptide (P = NS). Conclusions: Rotigaptide reduces myocardial infarction size in a porcine model and protects from IRI-related endothelial dysfunction in man. Rotigaptide may have therapeutic potential in the treatment of myocardial infarction.
Rotigaptide Infusion for the First 7 Days After Myocardial Infarction-Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border-Zone and Arrhythmia Inducibility
J Am Heart Assoc 2021 May 4;10(9):e020006.PMID:33870715DOI:10.1161/JAHA.120.020006.
Background Survivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction-reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis. Methods and Results Infarction-reperfusion surgery was carried out in male Sprague-Dawley rats followed by 7 days of Rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion-weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7-day postinfarction administration of Rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (Rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, P=0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: -5% versus -15%; P=0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, P=0.042), and remodeling of the 3-dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, P=0.013) and the dispersion (9° versus 12°, P=0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality. Conclusions Enhancement of gap junctions function by Rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation-induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarction management to reduce late arrhythmic risk.
Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia-Reperfusion Injury
Front Physiol 2021 Sep 13;12:726389.PMID:34588996DOI:10.3389/fphys.2021.726389.
Aims: Whether therapeutic hypothermia (TH) is proarrhythmic in preexisting failing hearts with acute ischemia-reperfusion (IR) injury is unknown. Additionally, the effectiveness of Rotigaptide on improving conduction slowing in hearts with IR injury is ambiguous. We investigated the electrophysiological effects of TH and Rotigaptide in failing rabbit hearts with acute IR injury and determined the underlying molecular mechanisms. Methods and Results: Heart failure was induced by right ventricular pacing (320 beats/min, 4 weeks). Rabbits with pacing-induced heart failure were randomly divided into TH (n = 14) and non-TH (n = 7) groups. The IR rabbit model was created by ligating the coronary artery for 60 min, followed by reperfusion for 15 min in vivo. Then, the hearts were excised quickly and Langendorff-perfused for simultaneous voltage and intracellular Ca2+ (Cai) optical mapping. Electrophysiological studies were conducted, and vulnerability to ventricular fibrillation (VF) was evaluated using pacing protocols. TH (33°C) was instituted after baseline studies, and electrophysiological studies were repeated. Rotigaptide (300 nM) was infused for 20 min, and electrophysiological studies were repeated under TH. Cardiac tissues were sampled for Western blotting. TH increased the dispersion and beat-to-beat variability of action potential duration (APD), aggravated conduction slowing, and prolonged Cai decay to facilitate spatially discordant alternans (SDA) and VF induction. Rotigaptide reduced the dispersion and beat-to-beat variability of APD and improved slowed conduction to defer the onset of arrhythmogenic SDA by dynamic pacing and elevate the pacing threshold of VF during TH. However, the effect of Rotigaptide on TH-enhanced VF inducibility was statistically insignificant. TH attenuated IR-induced dysregulation of protein expression, but its functional role remained uncertain. Conclusion: Therapeutic hypothermia is proarrhythmic in failing hearts with acute IR injury. Rotigaptide improves TH-induced APD dispersion and beat-to-beat variability and conduction disturbance to defer the onset of arrhythmogenic SDA and elevate the VF threshold by dynamic pacing, but these beneficial electrophysiological effects are unable to suppress TH-enhanced VF inducibility significantly.
Pharmacological modulation of gap junction function with the novel compound Rotigaptide: a promising new principle for prevention of arrhythmias
Basic Clin Pharmacol Toxicol 2007 Oct;101(4):215-30.PMID:17845503DOI:10.1111/j.1742-7843.2007.00123.x.
Existing anti-arrhythmic therapy is hampered by lack of efficacy and unacceptable side effects. Thus, ventricular tachycardia and fibrillation remains the strongest predictor of in-hospital mortality in patients with myocardial infarction. In atrial fibrillation, rhythm control with conventional ion channel blockers provide no therapeutic benefit relative to rate control. Several lines of research indicate that impaired gap junctional cell-to-cell coupling between neighbouring cardiomyocytes is critical for the development of cardiac re-entry arrhythmias. Rotigaptide is the first drug that has been developed to prevent arrhythmias by re-establishing gap junctional intercellular communication. During conditions with acute cardiac ischaemia, Rotigaptide effectively prevents induction of both ventricular and atrial tachyarrhythmia. Moreover, Rotigaptide effectively prevents ischaemia reperfusion arrhythmias. At the cellular level, Rotigaptide inhibits ischaemia-induced dephosphorylation of Ser297 and Ser368, which is considered important for the gating of connexin43 gap junction channels. No drug-related toxicity has been demonstrated at plasma concentrations 77,000 times above therapeutic concentrations. In rats and dogs, Rotigaptide reduces infarct size following myocardial infarction. A series of phase I trials has been completed in which Rotigaptide has been administered intravenously to ~200 healthy persons. No drug-related side effects have been demonstrated in healthy human beings. Clinical safety, tolerability and efficacy in patients with heart disease are being evaluated in ongoing clinical trials. Rotigaptide represents a pioneering pharmacological principle with a highly favourable preclinical and clinical safety profile, which makes this molecule a promising drug candidate for the prevention of cardiac arrhythmias.
Rotigaptide (ZP123) improves atrial conduction slowing in chronic volume overload-induced dilated atria
Basic Clin Pharmacol Toxicol 2006 Jul;99(1):71-9.PMID:16867174DOI:10.1111/j.1742-7843.2006.pto_432.x.
Chronic atrial dilation is associated with atrial conduction velocity slowing and an increased risk of developing atrial tachyarrhythmias. Rotigaptide (ZP123) is a selective gap junction modifier that increases cardiac gap junctional intercellular communication. We hypothesised that Rotigaptide treatment would increase atrial conduction velocity and reduce the inducibility to atrial tachyarrhythmias in a model of chronic volume overload induced chronic atrial dilatation characterized by atrial conduction velocity slowing. Chronic volume overload was created in Japanese white rabbits by arterio-venous shunt formation. Atrial conduction velocity and atrial tachyarrhythmias inducibility were examined in Langendorff-perfused chronic volume overload hearts (n=12) using high-resolution optical mapping before and after treatment with Rotigaptide. Moreover, expression levels of atrial gap junction proteins (connexin40 and connexin43) were examined in chronic volume overload hearts (n=6) and compared to sham-operated controls (n=6). Rotigaptide treatment significantly increased atrial conduction velocity in chronic volume overload hearts, however, Rotigaptide did not decrease susceptibility to the induction of atrial tachyarrhythmias. Protein expressions of Cx40 and Cx43 were decreased by 32% and 72% (P<0.01), respectively, in chromic volume overload atria compared to control. To conclude, Rotigaptide increased atrial conduction velocity in a rabbit model of chromic volume overload induced atrial conduction velocity slowing. The demonstrated effect of Rotigaptide on atrial conduction velocity did not prevent atrial tachyarrhythmias inducibility. Whether Rotigaptide may possess antiarrhythmic efficacy in other models of atrial fibrillation remains to be determined.