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Calhex 231 hydrochloride

negative allosteric modulator of Ca2+-sensing receptor (CaSR) CAS# 652973-93-8

Calhex 231 hydrochloride

2D Structure

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Calhex 231 hydrochloride

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Chemical Properties of Calhex 231 hydrochloride

Cas No. 652973-93-8 SDF Download SDF
PubChem ID 11849513 Appearance Powder
Formula C25H28Cl2N2O M.Wt 443.41
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 50 mM in DMSO
Chemical Name 4-chloro-N-[(1S,2S)-2-[[(1R)-1-naphthalen-1-ylethyl]amino]cyclohexyl]benzamide;hydrochloride
SMILES CC(C1=CC=CC2=CC=CC=C21)NC3CCCCC3NC(=O)C4=CC=C(C=C4)Cl.Cl
Standard InChIKey KZPHZSFSFANQIS-GRFVZBLOSA-N
Standard InChI InChI=1S/C25H27ClN2O.ClH/c1-17(21-10-6-8-18-7-2-3-9-22(18)21)27-23-11-4-5-12-24(23)28-25(29)19-13-15-20(26)16-14-19;/h2-3,6-10,13-17,23-24,27H,4-5,11-12H2,1H3,(H,28,29);1H/t17-,23+,24+;/m1./s1
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.
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.
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.

Biological Activity of Calhex 231 hydrochloride

DescriptionNegative allosteric modulator of the calcium sensing receptor (CaSR). Blocks increases in [3H]inositol phosphate levels elicited by wild-type hCasR activation (IC50= 0.39 μM in transiently transfected HEK293 cells).

Calhex 231 hydrochloride Dilution Calculator

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Preparing Stock Solutions of Calhex 231 hydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2552 mL 11.2762 mL 22.5525 mL 45.105 mL 56.3812 mL
5 mM 0.451 mL 2.2552 mL 4.5105 mL 9.021 mL 11.2762 mL
10 mM 0.2255 mL 1.1276 mL 2.2552 mL 4.5105 mL 5.6381 mL
50 mM 0.0451 mL 0.2255 mL 0.451 mL 0.9021 mL 1.1276 mL
100 mM 0.0226 mL 0.1128 mL 0.2255 mL 0.451 mL 0.5638 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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Background on Calhex 231 hydrochloride

Calhex 231 hydrochloride is a novel potent negative allosteric modulator of Ca2+-sensing receptor (CaSR) with an IC50 value of 0.39 µM to the increase in [3H]inositol phosphates induced by transiently expressed human wild-type CaSR in HEK293 cells [1].

The CaSR belongs to G-protein-coupled receptor (GPCR) class 3. CaSR is activated by charged molecules including spermidine, spermine, β-amyloid peptides, and several antibiotics. CaSR is also activated by Mg2+ and Ca2+ present in the extracellular fluids [1].

In HEK293 cells transiently expressing human WT CaSR, increasing the concentration of extracellular Ca2+ from 0.3 to 10 mM resulted in a 10-fold increase in [3H]IP accumulation, while no significant increase in [3H]IP accumulation was detected in cells transiently transfected with an empty control plasmid. The analysis of the dose-response curve resulted in an EC50 value of 3.4 ± 0.1 mM for Ca2+. Preincubation with Calhex 231 concentration-dependently inhibited the IP response to 10 mM Ca2+ in HEK293 cells expressing the human WT CaSR. The analysis of the dose-response curve resulted in an IC50 value of 0.39 ± 0.08 µM for Calhex 231 [1].

Calhex 231 produced significant myocyte depolarizations in segments of mesenteric arteries from both Zucker diabetic fatty (ZDF) and Zucker lean (ZL) rats. In the continuing presence of Calhex 231, hyperpolarizations to the calcium-sensing receptor (CaR) activator calindol were significantly reduced [2].

References:
[1].  Petrel C, Kessler A, Maslah F, et al. Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca2+-sensing receptor. Journal of Biological Chemistry, 2003, 278(49): 49487-49494.
[2].  Weston AH, Absi M, Harno E, et al. The expression and function of Ca2+-sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes. British journal of pharmacology, 2008, 154(3): 652-662.

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References on Calhex 231 hydrochloride

The expression and function of Ca(2+)-sensing receptors in rat mesenteric artery; comparative studies using a model of type II diabetes.[Pubmed:18414396]

Br J Pharmacol. 2008 Jun;154(3):652-62.

BACKGROUND AND PURPOSE: The extracellular calcium-sensing receptor (CaR) in vascular endothelial cells activates endothelial intermediate-conductance, calcium-sensitive K(+) channels (IK(Ca)) indirectly leading to myocyte hyperpolarization. We determined whether CaR expression and function was modified in a rat model of type II diabetes. EXPERIMENTAL APPROACH: Pressure myography, western blotting, sharp microelectrode and K(+)-selective electrode recordings were used to investigate the functional expression of the CaR and IK(Ca) in rat mesenteric arteries. KEY RESULTS: Myocyte hyperpolarization to the CaR activator calindol was inhibited by Calhex 231. U46619-induced vessel contraction elevated the extracellular [K(+)] around the myocytes, and inhibition of this 'K(+) cloud' by iberiotoxin was needed to reveal calindol-induced vasodilatations. These were antagonized by Calhex 231 and significantly smaller in Zucker diabetic fatty rat (ZDF) vessels than in Zucker lean (ZL) controls. Myocyte hyperpolarizations to calindol were also smaller in ZDF than in ZL arteries. In ZDF vessels, endothelial cell CaR protein expression was reduced; IK(Ca) expression was also diminished, but IK(Ca)-generated hyperpolarizations mediated by 1-EBIO were unaffected. CONCLUSIONS AND IMPLICATIONS: The reduced CaR-mediated hyperpolarizing and vasodilator responses in ZDF arteries result from a decrease in CaR expression, rather than from a modification of IK(Ca) channels. Detection of CaR-mediated vasodilatation required the presence of iberiotoxin, suggesting a CaR contribution to vascular diameter, that is, inversely related to the degree of vasoconstriction. Compromise of the CaR pathway would favour the long-term development of a higher basal vascular tone and could contribute to the vascular complications associated with type II diabetes.

N1-Benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: Development of 4-chlorophenylcarboxamide (calhex 231) as a new calcium sensing receptor ligand demonstrating potent calcilytic activity.[Pubmed:16913701]

J Med Chem. 2006 Aug 24;49(17):5119-28.

A structure-activity relationship (SAR) study was performed principally at the N1 position of N1-arylsulfonyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes, a new family of calcilytics acting at the calcium sensing receptor (CaSR). The most active compound in this series was the 4-(trifluoromethoxy)benzenesulfonyl derivative 7e, which displayed an IC50 of 5.4 +/- 0.5 microM with respect to the inhibition of calcium-induced tritiated inositol phosphate ([3H]IP) accumulation in Chinese hamster ovarian (CHO) cells expressing the CaSR. Replacement of the sulfonamide linkage of this compound by a carboxamide led to a 6-fold increase in activity (7m, IC50 = 0.9 +/- 0.2 microM). Among the carboxamides synthesized, one of the most active compounds was the 4-chlorophenylcarboxamide (1S,2S,1'R)-7n (Calhex 231, IC50 = 0.33 +/- 0.02 microM). The absolute configuration of (1S,2S,1'R)-7n was deduced from an X-ray crystallographic study of one of the diastereomers of compound 7d. The stereochemical preference for the (1S,2S,1'R)-isomers can be rationalized on the basis of a three-dimensional model of the calcilytic binding pocket of the CaSR. Removal of the C-1' methyl group or replacement of the 1-naphthyl group by a 2-naphthyl or biphenyl moiety led to appreciable loss of calcilytic activity. Compounds 7e, 7m, and Calhex 231 did not stimulate [3H]IP accumulation in CHO cells expressing or not expressing the CaSR.

Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca(2+)-sensing receptor.[Pubmed:14506236]

J Biol Chem. 2003 Dec 5;278(49):49487-94.

A model of the Ca2+-sensing receptor (CaSR) seven transmembrane domains was constructed based on the crystal structure of bovine rhodopsin. This model was used for docking (1S,2S,1'R)-N1-(4-chlorobenzoyl)-N2-[1-(1-naphthyl)ethyl]-1,2-diaminocyclohexane (Calhex 231), a novel potent negative allosteric modulator that blocks (IC50 = 0.39 microm) increases in [3H]inositol phosphates elicited by activating the human wild-type CaSR transiently expressed in HEK293 cells. In this model, Glu-8377.39 plays a pivotal role in anchoring the two nitrogen atoms of Calhex 231 and locating the aromatic moieties in two adjacent hydrophobic pockets delineated by transmembrane domains 3, 5, and 6 and transmembrane domains 1, 2, 3, and 7, respectively. To demonstrate its validity, we have mutated selected residues and analyzed the biochemical and pharmacological properties of the mutant receptors transfected in HEK293 cells. Two receptor mutations, F684A3.32 and E837A7.39, caused a loss of the ability of Calhex 231 to inhibit Ca2+-induced accumulation of [3H]inositol phosphates. Three other mutations, F688A3.36, W818A6.48, and I841A7.43, produced a marked increase in the IC50 of Calhex 231 for the Ca2+ response, whereas L776A5.42 and F821A6.51 led to a decrease in the IC50. Our data validate the proposed model for the allosteric interaction of Calhex 231 with the seven transmembrane domains of the CaSR. Interestingly, the residues at the same positions have been shown to delimit the antagonist-binding cavity of many diverse G-protein-coupled receptors. This study furthermore suggests that the crystal structure of bovine rhodopsin exhibits sufficient mimicry to the ground state of a very divergent class 3 receptor to predict the interaction of antagonists with the heptahelical bundle of diverse G-protein-coupled receptors.

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Negative allosteric modulator of the calcium-sensing receptor

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