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A 331440 dihydrochloride

H3 receptor antagonist,non-imidazole,high affinity CAS# 1049740-32-0

A 331440 dihydrochloride

Catalog No. BCC7963----Order now to get a substantial discount!

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Chemical structure

A 331440 dihydrochloride

3D structure

Chemical Properties of A 331440 dihydrochloride

Cas No. 1049740-32-0 SDF Download SDF
PubChem ID 16078942 Appearance Powder
Formula C22H29Cl2N3O M.Wt 422.39
Type of Compound N/A Storage Desiccate at -20°C
Solubility Soluble to 100 mM in water and to 20 mM in DMSO
Chemical Name 4-[4-[3-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]propoxy]phenyl]benzonitrile;dihydrochloride
SMILES CN(C)C1CCN(C1)CCCOC2=CC=C(C=C2)C3=CC=C(C=C3)C#N.Cl.Cl
Standard InChIKey XFPYVTSGYYMTFS-GHVWMZMZSA-N
Standard InChI InChI=1S/C22H27N3O.2ClH/c1-24(2)21-12-14-25(17-21)13-3-15-26-22-10-8-20(9-11-22)19-6-4-18(16-23)5-7-19;;/h4-11,21H,3,12-15,17H2,1-2H3;2*1H/t21-;;/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 A 331440 dihydrochloride

DescriptionHigh affinity histamine H3 receptor antagonist (Ki values are 21.7 and 22.7 nM for rat and human H3 receptors, respectively). Exhibits selectivity for human H3 over H1, H2 and H4 receptors (Ki values are 2940, 14400 and >10000 nM respectively). Shown to reduce weight in a diet-induced obesity model.

A 331440 dihydrochloride Dilution Calculator

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A 331440 dihydrochloride Molarity Calculator

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Preparing Stock Solutions of A 331440 dihydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.3675 mL 11.8374 mL 23.6748 mL 47.3496 mL 59.187 mL
5 mM 0.4735 mL 2.3675 mL 4.735 mL 9.4699 mL 11.8374 mL
10 mM 0.2367 mL 1.1837 mL 2.3675 mL 4.735 mL 5.9187 mL
50 mM 0.0473 mL 0.2367 mL 0.4735 mL 0.947 mL 1.1837 mL
100 mM 0.0237 mL 0.1184 mL 0.2367 mL 0.4735 mL 0.5919 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 A 331440 dihydrochloride

A-331440 is described here instead of A-331440 dihydrochloride. A-331440 is an antagonist of non-imidazole histamine H3 receptor with an IC50 value of 22.7 nM for human cortex histamine H3 [1].

Histamine, as a neurotransmitter, is important in homeostasis and physiology. In the CNS, histamine released has the potential to interact with H1, H2, H3 and possibly H4 receptors. All the receptors are G-protein coupled receptors [2].

In HEK 293 cells stably transfected with rat or human histamine H3 receptors, A-331440 was tested for its ability to antagonize increasing calcium mobilization in response to (R)-α-methylhistamine and showed pKb ± S.E.M. values of 7.38 ± 0.10 and 7.37 ± 0.29 for rat histamine H3 and human histamine H3, respectively [1].

In mice, treatment with A-331440 at a dose of 100 mg/kg resulted in piloerection and hypoactivity in the first 2 h, but diminished thereafter. In naive male CD-1 mice, administration with comparable doses of A-331440 i.p. also produced similar data. By day 28, mice treated with A-331440 at the intermediate dose weighed 35.7 ± 0.93 g with an average weight loss of 5.3 ± 0.99 g. The high dose of A-331440 (15 mg/kg, p.o., b.i.d.) produced a marked and sustained weight loss [1].

References:
[1].  Hancock AA, Bennani YL, Bush EN, et al. Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist. European journal of pharmacology, 2004, 487(1): 183-197.
[2].  Hancock AA, Diehl MS, Faghih R, et al. In vitro Optimization of Structure Activity Relationships of Analogues of A-331440 Combining Radioligand Receptor Binding Assays and Micronucleus Assays of Potential Antiobesity Histamine H3 Receptor Antagonists. Basic & clinical pharmacology & toxicology, 2004, 95(3): 144-152.

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References on A 331440 dihydrochloride

Antiobesity effects of A-331440, a novel non-imidazole histamine H3 receptor antagonist.[Pubmed:15033391]

Eur J Pharmacol. 2004 Mar 8;487(1-3):183-97.

Histamine affects homeostatic mechanisms, including food and water consumption, by acting on central nervous system (CNS) receptors. Presynaptic histamine H(3) receptors regulate release of histamine and other neurotransmitters, and histamine H(3) receptor antagonists enhance neurotransmitter release. A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile] is a histamine H(3) receptor antagonist which binds potently and selectively to both human and rat histamine H(3) receptors (K(i)<==25 nM). Mice were stabilized on a high-fat diet (45 kcal % lard) prior to 28-day oral b.i.d. dosing for measurement of obesity-related parameters. A-331440 administered at 0.5 mg/kg had no significant effect on weight, whereas 5 mg/kg decreased weight comparably to dexfenfluramine (10 mg/kg). A-331440 administered at 15 mg/kg reduced weight to a level comparable to mice on the low-fat diet. The two higher doses reduced body fat and the highest dose also normalized an insulin tolerance test. These data show that the histamine H(3) receptor antagonist, A-331440, has potential as an antiobesity agent.

In vitro optimization of structure activity relationships of analogues of A-331440 combining radioligand receptor binding assays and micronucleus assays of potential antiobesity histamine H3 receptor antagonists.[Pubmed:15447739]

Basic Clin Pharmacol Toxicol. 2004 Sep;95(3):144-52.

A-331440 [4'-[3-(3(R)-(dimethylamino)-pyrrolidin-1-yl)-propoxy]-biphenyl-4-carbonitrile], a potent and selective antagonist of histamine H3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo. Because this compound has highly favourable properties and potential as an antiobesity agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A-331440 for H3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A-331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A-331440 for H3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono- and di-fluorinated analogues (A-417022 [4'-[3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]propoxy]-3'-fluoro-1,1'-biphenyl-4- carbonitrile] and A-423579 [4'-[3-[(3R)-3-(dimethylamino)-1-pyrrolidinyl]-propoxy]-3',5'-difluoro-1,1'-biphe nyl-4-carbonitrile], respectively) were found to bind to H3 receptors at least as potently as A-331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A-331440 represented the most potent and potentially safest compounds for further evaluation as antiobesity leads. Preliminary findings with one of these examples, A-417022, in a mouse model of obesity are presented.

Description

Selective H3 antagonist

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