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RS-127445

RS-127445

Item no.	S2698-5
Manufacturer	Selleckchem
CASRN	199864-87-4
Amount	5 mg
Quantity options	10 mg 1 g 10 mM/1 ml 5 mg 50 mg 5 g
Category	Metabolism Regulation of Appetite Inhibitors & Compound Libraries Small Molecules
Type	Inhibitors
Specific against	other
Smiles	CC(C)C1=NC(=NC(=C1)C2=CC=C(C3=CC=CC=C32)F)N
ECLASS 10.1	32160490
ECLASS 11.0	32160490
UNSPSC	12000000
Alias	MT500
Similar products	RS-127445, 199864-87-3
Available
Storage Conditions	2 years -80 in solvent
Molecular Weight	281, 33
Administration	Oral for 2.5 h , intraperitoneal and intravenousroutes for 0.08 h
Animal Models	rats
Cell lines	HEK-293 cells expressing the human 5-HT2B receptor
Concentrations	10 uM
Dosages	5 mg/kg
Formulation	ethanol:pro-pylene glycol : water (10 : 50 : 40, v/v/v)
IC50	10.4 (pIC50) [1], 10.4 (pIC50) [1], 10.4 (pIC50) [1], 10.4 (pIC50) [1], 10.4 (pIC50) [1], 10.4 (pIC50) [1]
In vitro	RS-127445 is a novel high affinity, selective 5-HT2B receptor antagonist devoid of detectable intrinsic activity. RS-127445 is found to have nM affinity and 1000 fold selectivity for the 5-HT2B receptor. RS-127445 is thus among the highest affinity, most selective 5- HT2B receptor ligands. RS-127445 potently blocks the 5-HT evoked increase in inositol phosphate formation and blocks the 5-HT evoked increases in intracellular calcium concentrations with a potency 1000 times greater than that of yohimbine. [1]
In vivo	RS-127445 is readily absorbed with no obvious dose or route-dependent limitations and rapidly absorbed following both oral and intraperitoneal administration with peak plasma concentrations being achieved within 15 min of dosing. RS-127445 concentration in the plasma are achieved are proportional to the administered dose. RS-127445 administrated at dose of 5 mg/kg with approximately 60% of an intraperitoneal dose and 14% of the oral dose is bioavailable. RS-127445 concentration in the plasma is predicted to fully saturate accessible 5-HT2B receptors can be readily achieved and maintained in the rat. RS-127445 administered at 1 to 10 mg/kg with oral significantly inhibits visceral hypersensitivity up to 35 to 74% provoked by restraint stress. Oral RS-127445 produces a significant suppression of TNBS-induced visceral hypersensitivity (15 to 62% inhibition at 3 to 30 mg/ kg), although RS-127445 has no significant effect on the visceral nociceptive threshold of native rats. RS-127445 administrated orally with 1 to 30 mg/kg also dose -dependently reduce the restraint stress-induced defecation in native and TNBS-treated rats. [2]. RS-127445 inhibits colonic motility and defecation., [3]
Incubation Time	20 min
Kinase Assay	Radioligand binding, The selectivity of RS-127445 for 5-HT2B receptors is examined by testing the compound for affinity at over 100 additional ion channel or receptor binding sites. CHO-K1 cells expressing human 5-HT2A, 5-HT2B or 5-HT2C receptors are harvested using 2 mM EDTA in phosphate buffered saline. Cell membranes are prepared by four cycles of homogenization and centrifugation (48, 000xg for 15 min). Each assay is established so as to achieve steady state conditions and to optimize specific binding. For the 5-HT2A receptor, membranes from 1x106 cells are incubated with 0.2 nM [3 H]-ketanserin at 32 C for 60 min. Nonspecific binding is determined using 10 uM methysergide. For the 5-HT2B receptor, membranes from 1.5x106 cells are incubated with 0.2 nM [3 H]-5-HT at 48 C for 120 min. Nonspecific binding is determined using 10 uM 5-HT. For the 5-HT2Creceptor, membranes from 3x10 5 cells are incubated with 0.5 nM [3 H]-mesuler -gine at 32 C for 60 min. Nonspecific binding is determined using 10uM methysergide. Assays are terminated by vacuum filtration through glass fibre filters(GF/B) which has been pretreated with 0.1% polyethyleneimine. Total and bound radioactivity is determined by liquid scintillation counting. Greater than 90% specific binding is achieved in each of these assays.
Method	RS-127445, vehicle or other antagonists are pre-incubated with 240 ul of HEK-293 cells expressing the human 5-HT2B receptor suspension at 37 C for 20 min. HEK-293 cells are incubated with[3H]-myoinositol (1.67 uCi/ml) in 162 cm2 flasks overnight at 37 C in an inositol free Ham's F12 medium containing 10% dialyzed foetal bovine serum. The cells are harvested, washed five times with phosphate bufffered saline and resuspended in inositol free Ham's F12 media at density of approximately 3x103 cells/ml. The reactions are initiated by addition of 5-HT. Sixty minutes later, the reactions are terminated by adding 50 ul of ice-cold 20% perchloric acid, chilled in an ice-water bath for 10 min and then neutralized with 160ul of 1 N KOH. Each sample is diluted with 2 ml of 50 mM Tris-HCl, pH 7.4 at room temperature. The aqueous portion (2.2 ml) is transferred onto Dowex AG1X8 columns (1 ml, 1 : 1, w/v) which has been washed with 5 ml of distilled water. The columns are then washed with 18 ml of distilled water and the inositol phosphates are eluted with 3 ml of 1 N HCl. The eluted radioactivity is determined by liquid scintillation spectroscopy using a Packard 1900CA analyzer. [1]
Solubility (25C)	DMSO 56 mg/mL, Water <1 mg/mL, Ethanol 8 mg/mL
Information	RS-127445 (MT500) is a selective 5-HT2B receptor antagonist with pKi of 9.5 and pIC50 of 10.4, exhibits >1000-fold selectivity against other 5-HT receptors.
Chemical Name	4-(4-fluoronaphthalen-1-yl)-6-isopropylpyrimidin-2-amine

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