Org 25543 hydrochlorideGlyT2 inhibitor CAS# 495076-64-7 |
Quality Control & MSDS
3D structure
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| Cas No. | 495076-64-7 | SDF | Download SDF |
| PubChem ID | 10095215 | Appearance | Powder |
| Formula | C24H33ClN2O4 | M.Wt | 448.98 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | Soluble to 20 mM in water and to 100 mM in DMSO | ||
| Chemical Name | N-[[1-(dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-phenylmethoxybenzamide;hydrochloride | ||
| SMILES | CN(C)C1(CCCC1)CNC(=O)C2=CC(=C(C(=C2)OC)OCC3=CC=CC=C3)OC.Cl | ||
| Standard InChIKey | NIPQJILJYQVZJR-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C24H32N2O4.ClH/c1-26(2)24(12-8-9-13-24)17-25-23(27)19-14-20(28-3)22(21(15-19)29-4)30-16-18-10-6-5-7-11-18;/h5-7,10-11,14-15H,8-9,12-13,16-17H2,1-4H3,(H,25,27);1H | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Potent and selective glycine transporter type 2 (GlyT2) inhibitor (IC50 = 16 nM for hGlyT2). Displays no activity at GlyT1 or 56 other common biological targets (≥ 100 μM), in a glycine uptake assay in CHO cells. Ameliorates mechanical allodynia after partial sciatic nerve ligation injury in mice. |
Org 25543 hydrochloride Dilution Calculator
Org 25543 hydrochloride Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.2273 mL | 11.1364 mL | 22.2727 mL | 44.5454 mL | 55.6818 mL |
| 5 mM | 0.4455 mL | 2.2273 mL | 4.4545 mL | 8.9091 mL | 11.1364 mL |
| 10 mM | 0.2227 mL | 1.1136 mL | 2.2273 mL | 4.4545 mL | 5.5682 mL |
| 50 mM | 0.0445 mL | 0.2227 mL | 0.4455 mL | 0.8909 mL | 1.1136 mL |
| 100 mM | 0.0223 mL | 0.1114 mL | 0.2227 mL | 0.4455 mL | 0.5568 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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IC50:16 nM
Org 25543 hydrochloride is a potent and selective glycine transporter type 2 (GlyT2) inhibitor for hGlyT2. Two major subtypes of glycine transporter are type 1 (GlyT-1) and type 2 (GlyT-2) revealed by molecular cloning. The GlyT-2 transporter has a similar distribution to ssGlyR with being confined to the spinal cord and brain stem, whereas the GlyT-1 transporter has a wide distribution throughout the CNS.
In vitro: Org 25543 was identified as the most active compound in the library. Org 25543 has both cyclopentyl and BnO groups. As indicated by its favorable physicochemical parameters, Org 25543 exhibits a well penetration of bloodbrain barrier (logBB 0.6). Since Org 25543 also exhibits good metabolic stability (80% remaining after 30 min) in plasma and mouse hepatic microsomes, the compound should prove to be a valuable agent that might help to establish pharmacology of the GlyT-2 transporter [1].
In vivo: The administration of the antiallodynia effect of GlyT2 inhibitors ORG25543 and ALX1393 appeared without a time lag. The dose-dependent antiallodynia effect displayed by ORG25543 was effective in a limited-dose range. In glycinergic nerve terminals, dysfunction of GlyT2 function plays a very key role in insufficient transmitter loading of synaptic vesicles. However, no sign of hyperekplexia appeared by the administration of GlyT2 inhibitors. Pharmacological manipulation attenuated Glycine refilling in glycinergic nerve terminals in vivo, when reproduction of the antiallodynia effect by repeated treatment of ORG25543 (i.v.) with similar potency per time. [2].
Clinical trial: So far, no clinical study has been conducted.
References:
[1] Caulfield WL, Collie IT, Dickins RS, Epemolu O, McGuire R, Hill DR, McVey G, Morphy JR, Rankovic Z, Sundaram H. The first potent and selective inhibitors of the glycine transporter type 2. J Med Chem. 2001 Aug 16;44(17):2679-82.
[2] Morita K, Motoyama N, Kitayama T, Morioka N, Kifune K, Dohi T. Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice. J Pharmacol Exp Ther. 2008 Aug;326(2):633-45.
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Mianserin hydrochloride (Org GB 94) in the treatment of obsessional states.[Pubmed:881101]
J Int Med Res. 1977;5(4):289-91.
Nine patients with severe primary obsessional illness were treated with mianserin hydrochloride (Org GB 94), in a dose increasing to 20 mg three times daily, for 4 weeks. Six patients improved as assessed by a physician's global rating of improvement. The symptoms on a side-effects check list were less marked during treatment than they had been during the pre-treatment drug-free period.
Clinical experience with Org GB94 (mianserin hydrochloride), a new tetracyclic antidepressant.[Pubmed:669494]
Folia Psychiatr Neurol Jpn. 1978;32(2):171-83.
(1) Org GB94 (Mianserin hydrochloride), a new tetracyclic antidepressant, was administered to 21 patients with depression or with depressive states. (2) Remarkable antidepressive response was obtained with Org GB94 in moderate and mild forms of endogenous, involutional and senile depression. (3) The onset of action of Org GB94 was rapid. (4) Anticholinergic side effects were extremely rare and other untoward effects were mild in nature.
Mass fragmentographic assay of nanogram amounts of the antidepressant drug mianserin hydrochloride (Org GB 94) in human plasma.[Pubmed:863985]
J Chromatogr. 1977 May 1;143(3):289-97.
For the assay of the antidepressant compound mianserin hydrochloride (Org GB 94) in human plasma, a mass fragmentographic method, using the deuterated analogue as internal standard and a high-performance liquid chromatographie sample clean-up procedure has been developed. The assay specifications obtained are a lower limit for reliable measurements of 1 ng/ml, and accuracy of ca. 0.01 ng/ml, a precision of 6--7% and a capacity of about 60 samples per day. The applicability of the assay method is illustrated by measurements of single-dose and steady-state plasma levels in clinical experiments, demonstrating the possibility of monitoring plasma levels during at least 24 h after a single dose of 15 mg of Org GB 94. The mean steady-state plasma levels after a daily dose of 3 X 20 mg of Org GB 94 appeared to be remarkably constant with time: 38, 36 and 34 ng/ml after 2, 4, and 6 weeks of treatment of 18 depressed patients.
Antiarrhythmic, metabolic and hemodynamic effects of Org 6001 (3alpha-amino-5alpha-androstan-2beta-ol-17-one-hydrochloride) after coronary flow reduction in pigs.[Pubmed:633069]
J Pharmacol Exp Ther. 1978 Mar;204(3):634-44.
The antiarrhythmic activity of the aminosteroid Org 6001 was investigated in young pigs (20-28 kg). Ventricular arrhythmias were induced by restriction of the flow in the left anterior descending coronary artery (LAD) to 25% of its control value during a period of 30 minutes. Nine out of 30 control animals died in this period due to ventricular fibrillation. None of the 19 animals treated with Org 6001 (5-10 mg/kg) or the 12 animals treated with lidocaine (2.75-3.50 mg/kg) fibrillated. Moreover, the number of premature ventricular beats was greatly reduced in pretreated groups compared with the untreated group (P less than .001). The first derivative of left ventricular pressure decreased with 25% (P less than 0.001) after administration of Org 6001. However, during 30 minutes of LAD flow reduction to 25% of control, the adverse effects of Org 6001 were less than those of lidocaine. Myocardial lactate production indicated some delay in onset of ischemia. However, there was no indication that this beneficial effect was long-lasting. When after 30 minutes of LAD flow reduction to 25% of control, the LAD was completely occluded between its second and third branch, all untreated animals fibrillated within 120 minutes, whereas 4 of the 19 animals treated with Org 6001 and 3 of the 12 treated with lidocaine survived. It is concluded that Org 6001 has antiarrhythmic properties in the ischemic pig heart which compare favorably with those of lidocaine.
Spinal antiallodynia action of glycine transporter inhibitors in neuropathic pain models in mice.[Pubmed:18448867]
J Pharmacol Exp Ther. 2008 Aug;326(2):633-45.
Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for the treatment. Glycinergic neurons are localized in specific brain regions, including the spinal cord, where they play an important role in the regulation of pain signal transduction. Glycine transporter (GlyT)1, present in glial cells, and GlyT2, located in neurons, play roles in modulating glycinergic neurotransmission by clearing synaptically released glycine or supplying glycine to the neurons and thus could modify pain signal transmission in the spinal cord. In this study, we demonstrated that i.v. or intrathecal administration of GlyT1 inhibitors, cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-yl methyl)amino methylcarboxylic acid (ORG25935) or sarcosine, and GlyT2 inhibitors, 4-benzyloxy-3,5-dimethoxy-N-[1-(dimethylaminocyclopently)-methyl]benzamide (ORG25543) and (O-[(2-benzyloxyphenyl-3-fluorophenyl)methyl]-L-serine) (ALX1393), or knockdown of spinal GlyTs by small interfering RNA of GlyTs mRNA produced a profound antiallodynia effect in a partial peripheral nerve ligation model and other neuropathic pain models in mice. The antiallodynia effect is mediated through spinal glycine receptor alpha3. These results established GlyTs as the target molecules for the development of medicaments for neuropathic pain. However, these manipulations to stimulate glycinergic neuronal activity were without effect during the 4 days after nerve injury, whereas manipulations to inhibit glycinergic neuronal activity protected against the development of allodynia in this phase. The results implied that the timing of medication with their inhibitors should be considered, because glycinergic control of pain was reversed in the critical period of 3 to 4 days after surgery. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.
