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ORM-10103 Sale

目录号 : GC36814

ORM-10103 是 Na+/Ca2+ 交换体 (NCX) 特异性的抑制剂,ORM-10103 降低了 NCX 电流,在 -80 和 20 mV 下的 IC50 的估算值分别为 55 和 67 nM。

ORM-10103 Chemical Structure

Cas No.:488847-28-5

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产品描述

ORM-10103 is a specific inhibitor of the Na+/Ca2+ exchanger (NCX), which decreases the NCX current with estimated IC50s of 55 and 67 nM at -80 and at 20 mV, respectively[1][2]. IC50: 55 (NCX -80 mV ), 67 nM (NCX 20 mV)[2]

[1]. Jost N, et al. ORM-10103, a novel specific inhibitor of the Na+/Ca2+ exchanger, decreases early and delayed afterdepolarizations in the canine heart. Br J Pharmacol. 2013 Oct;170(4):768-78. [2]. Kohajda Z, et al. The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments. PLoS One. 2016 Nov 10;11(11):e0166041.

Chemical Properties

Cas No. 488847-28-5 SDF
Canonical SMILES O=[N+](C1=CN=C(OC2=CC=C3C(CCC(C4=CC=CC=C4)O3)=C2)C=C1)[O-]
分子式 C20H16N2O4 分子量 348.35
溶解度 DMSO: 250 mg/mL (717.67 mM) 储存条件 Store at -20°C
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Research Update

ORM-10103, a novel specific inhibitor of the Na+/Ca2+ exchanger, decreases early and delayed afterdepolarizations in the canine heart

Br J Pharmacol 2013 Oct;170(4):768-78.PMID:23647096DOI:10.1111/bph.12228.

Background and purpose: At present there are no small molecule inhibitors that show strong selectivity for the Na(+) /Ca(2+) exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca(2+) currents and on the formation of early and delayed afterdepolarizations. Experimental approach: Ion currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. Key results: ORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 μM), ORM-10103 did not significantly change the L-type Ca(2+) current or the maximum rate of depolarization (dV/dtmax ), indicative of the fast inward Na(+) current. At 10 μM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca(2+) current. ORM-10103 did not influence the Na(+) /K(+) pump or the main K(+) currents of canine ventricular myocytes, except the rapid delayed rectifier K(+) current, which was slightly diminished by the drug at 3 μM. The amplitudes of pharmacologically- induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 μM) in a concentration-dependent manner. Conclusions and implications: ORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events.

ORM-10103: a significant advance in sodium-calcium exchanger pharmacology?

Br J Pharmacol 2013 Oct;170(4):765-7.PMID:23848255DOI:10.1111/bph.12299.

The sodium-calcium exchanger (NCX) is an electrogenic transporter that is widely expressed in different tissues. In the heart, the NCX plays important roles in calcium ion homeostasis, excitation-contraction coupling and the electrophysiological properties of cardiac myocytes. Precise determination of the roles of the NCX has somewhat been hampered by a lack of selective small molecule inhibitors. In this issue of the BJP, Jost and colleagues present data on a new NCX inhibitor, ORM-10103, which has submicromolar EC50 values against cardiac forward and reverse exchange activity. The compound exhibits improved selectivity over existing small molecule NCX inhibitors and, in particular, appears to be without effect on L-type calcium channels at high concentrations. ORM-10103 could therefore have significant value for studies of the (patho)physiological roles of the NCX in the heart. Further pharmacological studies are required to investigate the actions of ORM-10103 on cardiac cells and tissues and to determine its effects on non-cardiac NCX isoforms.

Efficacy of selective NCX inhibition by ORM-10103 during simulated ischemia/reperfusion

Eur J Pharmacol 2014 Oct 5;740:539-51.PMID:24975099DOI:10.1016/j.ejphar.2014.06.033.

In this study we evaluated the effects of selective Na+/Ca2+ exchanger (NCX) inhibition by ORM-10103 on the [Ca2+]i transient (CaT), action potential (AP), and cell viability in isolated canine ventricular cardiomyocytes exposed to a simulated ischemia/reperfusion protocol performed either alone (modeling moderate low-flow ischemia) or with simultaneous strophantidine challenge (modeling more severe low-flow ischemia). CaTs were monitored using a Ca2+-sensitive fluorescent dye, APs were recorded by intracellular microelectrodes, and anaerobic shifts in cellular metabolism were verified via monitoring native NADH fluorescence. Simulated ischemia increased the NADH fluorescence, reduced the amplitudes of the AP and CaT and induced membrane depolarization. APs moderately shortened, CaTs prolonged. Diastolic [Ca2+]i ([Ca2+]iD) level increased significantly during ischemia and further elevated following strophantidine application. Reperfusion normalized the NADH level, the amplitude of the AP and duration of the [Ca2+]i transient, but only partially restored action potential triangulation and the amplitude of the CaT. [Ca2+]iD decreased in untreated, but further increased in strophantidine-treated cells. 10 µM ORM-10103 significantly reduced the ischemic [Ca2+]i raise in both untreated and strophantidine-treated cells. During reperfusion ORM-10103 decreased [Ca2+]i and eliminated its diastolic elevation in untreated and strophantidine-treated cardiomyocytes. Following the application of ORM-10103 the detrimental effect of ischemia/reperfusion on cell viability and the reperfusion-induced increase in AP and CaT variabilities were substantially reduced, but ischemia-induced shifts in AP morphology were barely influenced. In conclusion, selective NCX inhibition by ORM-10103 is highly effective against ischemia/reperfusion induced pathologic alterations in [Ca2+]i homeostasis, however, it fails to normalize untoward arrhythmogenic changes in AP morphology.

Paradoxical Effects of Sodium-Calcium Exchanger Inhibition on Torsade de Pointes and Early Afterdepolarization in a Heart Failure Rabbit Model

J Cardiovasc Pharmacol 2018 Aug;72(2):97-105.PMID:29738372DOI:10.1097/FJC.0000000000000598.

Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis of secondary Ca rise and EAD-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca rise, EADs development, and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM-10103 had a neutral effect on the amplitude of secondary Cai rise in control and heart failure groups. In this model, most EADs generated from long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced premature ventricular beat burden but was unable to suppress secondary Ca rise, EADs development, or inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.

Comparison of the efficiency of Na+/Ca2+ exchanger or Na+/H+ exchanger inhibition and their combination in reducing coronary reperfusion-induced arrhythmias

J Physiol Pharmacol 2015 Apr;66(2):215-26.PMID:25903952doi

During ischaemia/reperfusion, the rise in [Na(+)](i), induced by simultaneous depression of the Na(+)/K(+)-ATPase and activation of the Na(+)/H(+) exchanger (NHE), shifts the Na(+)/Ca(2+) exchanger (NCX) into reverse transport mode, resulting in Ca(2+)(i)overload, which is a critical factor in enhancing the liability to cardiac arrhythmias. The inhibition of NHE, and recently NCX has been suggested to effectively protect the heart from reperfusion-induced arrhythmias. In this study, we investigated and compared the efficacy of individual or the simultaneous inhibition of the NHE and NCX against reperfusion-induced arrhythmias in Langendorff-perfused rat hearts by applying a commonly used regional ischaemia-reperfusion protocol. The NHE and NCX were inhibited by cariporide and SEA0400 or the novel, more selective ORM-10103, respectively. Arrhythmia diagrams calculated for the reperfusion period were analysed for the incidence and duration of extrasystoles (ESs), ventricular tachycardia (VT) and ventricular fibrillation (VF). NHE inhibition by cariporide was highly efficient in reducing the recorded reperfusion-induced arrhythmias. Following the application of SEA0400 or ORM-10103, the number and duration of arrhythmic periods were efficiently or moderately decreased. While both NCX inhibitors effectively reduced ESs, the most frequently triggered arrhythmias, they exerted limited or no effect on VTs and VFs. Of the NCX inhibitors, ORM-10103 was more effective. Surprisingly, the simultaneous inhibition of the NCX and NHE failed to significantly improve the antiarrhythmic efficacy reached by NCX blockade alone. In conclusion, although principal simultaneous NHE+NCX inhibition should be highly effective against all types of the recorded reperfusion-induced arrhythmias, NCX inhibitors, alone or in combination with cariporide, seem to be moderately suitable to provide satisfactory cardioprotection - at least in the present arrhythmia model. Since ORM-10103 and SEA0400 are known to effectively inhibit after-depolarisations, it is suggested that their efficacy and that of other NCX inhibitors may be higher and more pronounced in the predominantly Ca(2+)(i)-dependent triggered arrhythmias.