AZ 10606120 dihydrochloride

Potent P2X7 receptor antagonist CAS# 607378-18-7

AZ 10606120 dihydrochloride

Catalog No. BCC6005----Order now to get a substantial discount!

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Chemical structure

AZ 10606120 dihydrochloride

3D structure

Chemical Properties of AZ 10606120 dihydrochloride

Cas No. 607378-18-7 SDF Download SDF
PubChem ID 56972227 Appearance Powder
Formula C25H36Cl2N4O2 M.Wt 495.48
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 25 mM in water and to 100 mM in DMSO
Chemical Name 2-(1-adamantyl)-N-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide;dihydrochloride
SMILES C1C2CC3CC1CC(C2)(C3)CC(=O)NC4=CC=CC5=C4C=CC(=N5)NCCNCCO.Cl.Cl
Standard InChIKey BVFONFUUWORSPO-UHFFFAOYSA-N
Standard InChI InChI=1S/C25H34N4O2.2ClH/c30-9-8-26-6-7-27-23-5-4-20-21(28-23)2-1-3-22(20)29-24(31)16-25-13-17-10-18(14-25)12-19(11-17)15-25;;/h1-5,17-19,26,30H,6-16H2,(H,27,28)(H,29,31);2*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.
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 AZ 10606120 dihydrochloride

DescriptionPotent P2X7 receptor antagonist (KD values are 1.4 and 19 nM at human and rat P2X7 receptors respectively). Binds in a positive cooperative manner to sites distinct from, but coupled to, the ATP binding site and acts as a negative allosteric modulator. Inhibits tumor growth and displays antiangiogenic effects in mice.

AZ 10606120 dihydrochloride Dilution Calculator

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Preparing Stock Solutions of AZ 10606120 dihydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0182 mL 10.0912 mL 20.1824 mL 40.3649 mL 50.4561 mL
5 mM 0.4036 mL 2.0182 mL 4.0365 mL 8.073 mL 10.0912 mL
10 mM 0.2018 mL 1.0091 mL 2.0182 mL 4.0365 mL 5.0456 mL
50 mM 0.0404 mL 0.2018 mL 0.4036 mL 0.8073 mL 1.0091 mL
100 mM 0.0202 mL 0.1009 mL 0.2018 mL 0.4036 mL 0.5046 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 AZ 10606120 dihydrochloride

KD: 1.4 nM and 1.9 nM for human and rat P2X7 receptors, respectivley

The P2X7 receptor has intriguing biophysical properties, activates a diverse range of cellular events and mediates a wide range of functional effects. The P2X7 receptor is an ATP-gated ion channel known for its cytotoxic activity. However, recent evidence suggests a role for P2X7 in cell proliferation. AZ 10606120 is a P2X7 receptor antagonist.

In vitro: Binding of [3H]-AZ 10606120 was higher in membranes prepared from cells expressing P2X7 receptors than from control cells and was inhibited by ATP suggesting labelled sites represented human P2X7 receptors. Binding was reversible, saturable and modulated by P2X7 receptor ligands. The positive cooperativity observed suggests that binding of AZ 10606120 to one subunit in the P2X7 receptor complex enhances subsequent binding to other P2X7 subunits in the same complex. The negative cooperative effects of ATP suggest that ATP and AZ 10606120 bind at separate, interacting, sites on the P2X7 receptor [1].

In vivo: Intratumor injection of AZ10606120 caused a strong inhibition of tumor growth in B16-inoculated C57Bl/6 mice and caused in parallel a large reduction in VEGF staining and vessel formation [2].

Clinical trial: Up to now, AZ 10606120 is still in the preclinical development stage.

Reference:
[1] AD Michel, LJ Chambers, WC Clay, JP Condreay, DS Walter and IP Chessell.  Direct labelling of the human P2X7 receptor and identification of positive and negative cooperativity of binding. British Journal of Pharmacology (2007) 151, 84–95
[2] Elena Adinolfi, Lizzia Raffaghello, Anna Lisa Giuliani, Luigi Cavazzini, Marina Capece, Paola Chiozzi, Giovanna Bianchi, Guido Kroemer, Vito Pistoia, and Francesco Di Virgilio.  Expression of P2X7 Receptor Increases In Vivo Tumor Growth. Cancer Res; 72(12); 2957–69.

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References on AZ 10606120 dihydrochloride

Expression of P2X7 receptor increases in vivo tumor growth.[Pubmed:22505653]

Cancer Res. 2012 Jun 15;72(12):2957-69.

The P2X7 receptor is an ATP-gated ion channel known for its cytotoxic activity. However, recent evidence suggests a role for P2X7 in cell proliferation. Here, we found that P2X7 exhibits significant growth-promoting effects in vivo. Human embryonic kidney cells expressing P2X7 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo, and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the P2X7 inhibitor-oxidized ATP. The accelerated growth of P2X7-expressing tumors was characterized by increased proliferation, reduced apoptosis, and a high level of activated transcription factor NFATc1. These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of VEGF. The growth and neoangiogenesis of P2X7-expressing tumors was blocked by intratumoral injection of the VEGF-blocking antibody Avastin (bevacizumab), pharmacologic P2X7 blockade, or P2X7 silencing in vivo. Immunohistochemistry revealed strong P2X7 positivity in several human cancers. Together, our findings provide direct evidence that P2X7 promotes tumor growth in vivo.

Negative and positive allosteric modulators of the P2X(7) receptor.[Pubmed:18071294]

Br J Pharmacol. 2008 Feb;153(4):737-50.

BACKGROUND AND PURPOSE: Antagonist effects at the P2X(7) receptor are complex with many behaving in a non-competitive manner. In this study, the effects of N-[2-({2-[(2-hydroxyethyl)amino]ethyl}amino)-5-quinolinyl]-2-tricyclo[3.3.1.1(3,7 )]dec-1-ylacetamide (compound-17) and N (2)-(3,4-difluorophenyl)-N (1)-[2-methyl-5-(1-piperazinylmethyl)phenyl]glycinamide dihydrochloride (GW791343) on P2X(7) receptors were examined and their mechanism of action explored. EXPERIMENTAL APPROACH: Antagonist effects were studied by measuring agonist-stimulated ethidium accumulation in cells expressing human or rat recombinant P2X(7) receptors and in radioligand binding studies. KEY RESULTS: Compound-17 and GW791343 were non-competitive inhibitors of human P2X(7) receptors. Receptor protection studies using decavanadate and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) showed that neither compound-17 nor GW791343 competitively interacted at the ATP binding site and so were probably negative allosteric modulators of the P2X(7) receptor. GW791343 prevented the slowly reversible blockade of the human P2X(7) receptor produced by compound-17 and inhibited [(3)H]-compound-17 binding to the P2X(7) receptor suggesting they may bind to similar or interacting sites. At rat P2X(7) receptors, compound-17 was a negative allosteric modulator but the predominant effect of GW791343 was to increase agonist responses. Antagonist interaction and radioligand binding studies revealed that GW791343 did not interact at the ATP binding site but did interact with the compound-17 binding site suggesting that GW791343 is a positive allosteric modulator of the rat P2X(7) receptor. CONCLUSIONS: Compound-17 was a negative allosteric modulator of human and rat P2X(7) receptors. GW791343 was a negative allosteric modulator of the human P2X(7) receptor but at the rat P2X(7) receptor its predominant effect was positive allosteric modulation. These compounds should provide valuable tools for mechanistic studies on P2X(7) receptors.

Direct labelling of the human P2X7 receptor and identification of positive and negative cooperativity of binding.[Pubmed:17339830]

Br J Pharmacol. 2007 May;151(1):103-14.

BACKGROUND AND PURPOSE: The P2X(7) receptor exhibits complex pharmacological properties. In this study, binding of a [(3)H]-labelled P2X(7) receptor antagonist to human P2X(7) receptors has been examined to further understand ligand interactions with this receptor. EXPERIMENTAL APPROACH: The P2X(7) receptor antagonist, N-[2-({2-[(2-hydroxyethyl)amino]ethyl}amino)-5-quinolinyl]-2-tricyclo[3.3.1.1(3,7 )]dec-1-ylacetamide (compound-17), was radiolabelled with tritium and binding studies were performed using membranes prepared from U-2 OS or HEK293 cells expressing human recombinant P2X(7) receptors. KEY RESULTS: Binding of [(3)H]-compound-17 was higher in membranes prepared from cells expressing P2X(7) receptors than from control cells and was inhibited by ATP suggesting labelled sites represented human P2X(7) receptors. Binding was reversible, saturable and modulated by P2X(7) receptor ligands (Brilliant Blue G, KN62, ATP, decavanadate). Furthermore, ATP potency was reduced in the presence of divalent cations or NaCl. Radioligand binding exhibited both positive and negative cooperativity. Positive cooperativity was evident from bell shaped Scatchard plots, reduction in radioligand dissociation rate by unlabelled compound-17 and enhancement of radioligand binding by KN62 and unlabelled compound-17. ATP and decavanadate inhibited binding in a negative cooperative manner as they enhanced radioligand dissociation. CONCLUSIONS: These data demonstrate that human P2X(7) receptors can be directly labelled and provide novel insights into receptor function. The positive cooperativity observed suggests that binding of compound-17 to one subunit in the P2X(7) receptor complex enhances subsequent binding to other P2X(7) subunits in the same complex. The negative cooperative effects of ATP suggest that ATP and compound-17 bind at separate, interacting, sites on the P2X(7) receptor.

Agonist potency at P2X7 receptors is modulated by structurally diverse lipids.[Pubmed:17700717]

Br J Pharmacol. 2007 Oct;152(4):523-37.

BACKGROUND AND PURPOSE: The P2X(7) receptor exhibits a high degree of plasticity with agonist potency increasing after prolonged receptor activation. In this study we investigated the ability of lipids to modulate agonist potency at P2X(7) receptors. EXPERIMENTAL APPROACH: A variety of lipids, including lysophosphatidylcholine, sphingosylphosphorylcholine and hexadecylphosphorylcholine were studied for their effect on P2X(7) receptor-stimulated ethidium bromide accumulation in cells expressing human recombinant P2X(7) receptors and on P2X(7) receptor-stimulated interleukin-1 beta (IL1 beta) release from THP-1 cells. The effects of the lipids were also assessed in radioligand binding studies on human P2X(7) receptors. KEY RESULTS: At concentrations (3-30 microM) below the threshold to cause cell lysis, the lipids increased agonist potency and/or maximal effects at P2X(7) receptors in both ethidium accumulation and IL1 beta release studies. There was little structure activity relationship (SAR) for this effect and sub-lytic concentrations of Triton X-100 partially mimicked the effects of the lipids. The lipids caused cell lysis and increased intracellular calcium at higher concentrations (30-100 microM) which complicated interpretation of their effects in functional studies. However, the lipids (3-100 microM) also increased agonist potency 30-100 fold in radioligand binding studies. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that a diverse range of lipids increase agonist potency at the P2X(7) receptor in functional and binding studies. The broad SAR, including the effect of Triton X-100, suggests this may reflect changes in membrane properties rather than a direct effect on the P2X(7) receptor. Since many of the lipids studied accumulate in disease states they may enhance P2X(7) receptor function under pathophysiological conditions.

Description

AZ10606120 dihydrochloride is a selective, high affinity antagonist for P2X7 receptor (P2X7R) at human and rat with an IC50 of ~10 nM. AZ10606120 dihydrochloride is little or no effect at other P2XR subtypes. AZ10606120 dihydrochloride has anti-depressant effects and reduces tumour growth.

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